Investigator Awards in Science

Investigator Awards in Science: people we've funded

2016

July

Full details of the Investigator Awards listed below will be added shortly. 

Professor Mark Achtman

University of Warwick

Deep evolutionary history of bacterial pathogens

Dr Elizabeth Bayne

University of Edinburgh

Understanding mechanisms of small RNA mediated silencing

Dr Ian Brierley

University of Cambridge

Protein trans-activation of ribosomal frameshifting: a new paradigm in gene expression

Professor David Glover

University of Cambridge

Duplication and cellular functions of Drosophila Centrioles

Dr Trevor Graham and Dr Andrea Sottoriva

Queen Mary University of London and Institute of Cancer Research

Evolutionary Predictions In Colorectal Cancer (EPICC)

Professor Tracy Hussell

University of Manchester

Pathogenic airway macrophage adaptation in the chronically inflamed lung

Dr Jan Löwe

MRC Laboratory of Molecular Biology, University of Cambridge

Actin-like cytoskeletal systems in bacteria and archaea

Dr Rachel McLoughlin

Trinity College Dublin

Staphylococcus aureus induced immunosuppressive memory: consequences for bug and for host

Dr Duncan Odom and Dr Paul Flicek

University of Cambridge and European Bioinformatics Institute

Regulatory potential of repeat elements in the evolution of tissue-specific transcription

Professor Frances Platt

University of Oxford

The NPC lysosomal pathway as a novel hub in host: pathogen interactions

Professor Sarah Reece

University of Edinburgh

Parasite offence or host defence? The roles of biological rhythms in malaria infection

Professor Beatriz Rico

King's College London

Assembly and organisation of inhibitory networks in the cerebral cortex

Dr Rachel Simmonds

University of Surrey

Investigating the role of coagulation in the pathogenesis of Buruli ulcer

Dr Nicholas Timpson

University of Bristol

What lies behind the causal impact of Body Mass Index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping

Professor Martin Tobin

University of Leicester

Large-scale genomic epidemiology approaches to study the natural history of lung function and COPD

Professor Hugh Willison

University of Glasgow

Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromes

 

 

April

Full details of the Investigator Awards listed below will be added shortly. 

Professor Oreste Acuto

University of Oxford

Initiation, dynamic control and long-term consequences of T-cell antigen receptor signalling: understanding etiology and therapy of immune diseases

Professor Sir Tom Blundell

University of Cambridge

Achieving selectivity in space and time with DNA double-strand break response and repair: molecular stages and scaffolds come with strings attached

Professor Pedro Carvalho

University of Oxford

The mechanisms and physiology of ER-associated protein degradation

Dr Claudia Clopath

Imperial College London

Memory across multiple timescales

Dr Francesco Colucci and Professor Ashley Moffett

University of Cambridge

Maternal NK cell recognition of the placenta determines reproductive outcome

Professor Anke Ehlers and Professor David Clark

University of Oxford

Joint Principal Research Fellowship Renewal and Investigator Award
Advancing cognitive therapy for anxiety disorders and PTSD

Dr Jonathan Grimes

University of Oxford

A mechanistic understanding of the replication of influenza virus

Professor Iain Hagan

University of Manchester

Spatial and temporal control of mitotic commitment

Dr Leo James

University of Cambridge

Host physiology of the intracellular humoral immune response

Professor Ben Luisi

University of Cambridge

The molecular machinery of RNA metabolism and riboregulation in bacteria

Professor Jane McKeating

University of Birmingham

Defining the role of hypoxia-inducible factors in viral replication and pathogenesis

Professor Jeremy Mottram

University of York

Kinome-wide functional analysis of Leishmania growth and differentiation

Dr Matthew Neale

University of Sussex

Spatial regulation of meiotic recombination

Professor Matthew Nolan

University of Edinburgh

Intra- and inter-layer entorhinal circuit mechanisms for estimating location

Dr Markus Ralser

Francis Crick Institute

Metabolic co-operation in eukaryotes: when metabolic networks operate non-cell autonomously

Professor Steven Riley

Imperial College London

The life course of human immune responses to influenza infection and vaccination

Professor Antal Rot

University of York

Physiological and pathophysiological roles of DARC (ACKR1) in haematopoiesis

Professor David Sherratt

University of Oxford

Co-ordination of chromosome unlinking and segregation

Professor Kenneth Smith

University of Cambridge

A new biology of clinical outcome in immune-mediated disease

Dr Anne Straube

University of Warwick

Self-organisation of acentrosomal microtubule arrays

Dr Martin Turner

Babraham Institute

Regulation of B-cell activation and differentiation by AU-rich element RNA binding proteins

Dr Alessandro Vannini

Institute of Cancer Research

Architectural role of RNA polymerase III promoters and associated factors in shaping and organising the human genome

 

2015

December

Professor Luke Alphey

Pirbright Institute

Developing methods for driving beneficial genetic traits into vector populations

Mosquito-borne diseases cause severe morbidity and mortality around the world. Dengue is relentlessly increasing in incidence and severity, and chikungunya and Zika viruses have recently invaded the Americas. Genetic control methods potentially offer new, sustainable, environmentally friendly control measures. One possibility is to modify the wild mosquito population so that it is less able to transmit specific diseases. This would leave the mosquito population intact and would be a minimalist intervention in the ecosystem; one aspect of which is that no ‘empty niche’ would be left open for another vector species. Professor Alphey aims to develop methods to make such changes to wild populations, which will require that most of the mosquitoes in the target population carry the disease-resistance gene and continue to do so for many generations. The aim is to develop genetic systems that will persist in target populations, but not invade adjacent, semi-isolated populations. This would allow local action to be taken in modifying selected vector mosquito populations. 

Professor David Beech

University of Leeds

Understanding vascular mechanical sensitivity

One of the most critical aspects of the endothelial cell is its sensitivity to mechanical forces, which arise because of the beating heart, tissue remodelling, external insults and other factors. Piezo1, a large multi-pass membrane protein, has been linked to calcium signalling and mechanical sensitivity, and was found to be required for one of the earliest responses to sheer stress: activation of non-selective cationic channels to allow calcium entry. Piezo1 is considered to be pivotal in both the detection of physical force and its transduction into appropriate vascular architecture. With this award, Professor Beech aims to uncover new mechanistic understanding of the Piezo1 protein and to uncover how vascular mechanical sensitivity works in physiology. This research will lead to a greater understanding of the endothelial cell, the primary architect and architecture of vasculature in the brain, heart and all other major organs.

Professor Robert Brownstone

University College London

Tuning spinal motoneurons for movement

In order to move, our muscles contract with precise forces and coordination. When these processes are disrupted by injury or disease, movements are impaired, resulting in decline in quality of life. To generate appropriate forces, the electrical activity of nerve cells in the spinal cord is finely tuned. Spinal motor neurons connect the central nervous system with muscles, and their activity causes muscles to contract with particular forces. Interestingly, the properties of each motor neuron match those of the type of muscle fibres it innervates. Professor Brownstone will investigate the mechanisms that govern the process of motor neuron tuning. In particular, he will focus on the role played by local spinal cord circuits in ensuring that motor neurons develop the electrical properties required for appropriate force generation. This knowledge will form the foundation of strategies aimed at correcting the neurological control of force production in diseases in which this is impaired.

Professor Antony Carr

University of Sussex

Replication arrest, restart and genome instability

A single human cell contains approximately 12,000,000,000 DNA bases, which must each be accurately copied uncountable times during development. To maintain an adult, this copying occurs billions of times daily. DNA replication is remarkably accurate, but errors do occur and the subsequent genetic alterations can result in genetic and somatic disorders such as cancer. Professor Carr aims to understand the specific mechanisms underlying replication-dependent genomic instability. With a major focus on restarted replication forks, he will combine classical and molecular genetics with super-resolution microscopy to explore new concepts in genome stability. He will establish new assays to understand replication dynamics and novel experimental systems, to explore the nature and consequences of restarted replication forks and how they merge with active replication forks.

Professor Daniel Davis

University of Manchester

The nanoscale organisation of immune cell surfaces in health and disease

Super-resolution microscopes, celebrated in the 2014 Nobel Prize for Chemistry, are one of the tools that allow us to study immune cells in unprecedented detail. Recently, Professor Davis’s research team has used these microscopes to study the changing arrangements of molecules on the surface of immune cells as they survey other cells for signs of disease. They will now compare how the surface organisation of specific immune cells, called natural killer cells and macrophages, varies in health and disease, as well as in individuals with variations in immune system genes. The team will test how the structure of cell surfaces impacts the thresholds at which immune responses are turned on and off. As well as understanding how immune cells work, the aim is to uncover new ways in which medicines can nudge their activity up or down.

Professor Ulrike Eggert

Credit: David Tett

King's College London

Manipulating membranes: how do lipids interact with the cytoskeleton?

Lipids are important molecules with many essential functions. They are major constituents of all membrane compartments and are key determinants of their interactions with other cellular structures. Cells produce thousands of different lipids and hundreds of proteins to synthesise and transport these lipids. Lipid dysfunction is associated with numerous diseases, but the importance of lipids has been under-appreciated in cell biology. Professor Eggert will use this award to investigate the role of lipids, and particularly their side chains, in processes controlled by the cytoskeleton, such as cell division, movement and cell-cell interactions. Initially focusing on cell division, which requires the participation of lipids and membranes, she will combine multiple methods from chemical biology, cell biology and biophysics to elucidate the specific roles of lipids in modulating the functions of membrane-associated proteins that play different, yet essential, roles in cytokinesis.

Dr Denise Fitzgerald

Queen's University Belfast

Harnessing T cells to remyelinate the central nervous system

Myelin, the supportive insulation that wraps around nerve axons in the central nervous system (CNS) is produced by oligodendrocytes. When myelin is damaged in conditions like Multiple Sclerosis (MS), a repair response can be activated. This should result in the maturation of oligodendrocyte progenitor cells into myelin-regenerating oligodendrocytes that re-ensheath axons (remyelination) and restore neurological function. However, when remyelination fails, as is common in MS, patients can develop permanent disability. Recently, immune cells have been implicated in regulation of this regenerative process. However, little is known about the role of T cells in remyelination, despite decades of research into T-cell-mediated myelin damage (demyelination). By combining neuroscience, immunology and regenerative biology, Dr Fitzgerald will determine how different types of T cells influence remyelination, and examine whether the progression of demyelinating diseases like MS alters these fundamental functions of T cells in CNS regeneration.

Professor Greg Hannon

University of Cambridge

A small RNA-based innate immune system guards germ cell genomes

One of the most fundamental biological imperatives is faithful transmission of the genome from parent to progeny. Transposons - parasitic mobile genetic elements - threaten this process and represent one of the most pervasive embodiments of the host-parasite relationship. Their drive is to propagate in germ cells; failure to control these elements can lead to sterility. Professor Hannon discovered the piRNA pathway, a small RNA-based innate immune system that recognises and silences transposons in germ cells. He will use this award to study the action mechanism of piRNAs. Specifically, he will investigate how maternally-inherited piRNA populations in drosophila influence transposon silencing in germ and somatic cells, how piRNAs are processed, and establish how they bring about long-term transcriptional repression.

Professor Richard Hartley and Dr Michael Murphy 

 

University of Glasgow and University of Cambridge

Exploring mitochondrial metabolism in health and disease using targeted biological chemistry

Mitochondrial dysfunction contributes to pathologies ranging from the acute, such as cardiac ischaemia-reperfusion injury, to chronic, such as the metabolic syndrome and the degenerative diseases that occur with ageing. Pathology is often associated with increased levels of reactive species such as superoxide and hydrogen peroxide. However, the molecular mechanisms by which elevated mitochondrial reactive species and disruption to redox signalling contribute to pathology are unclear and disputed. This is largely because reactive species and redox changes are difficult to assess in vivo and therapeutic options are limited. Professor Hartley and Dr Murphy aim to determine the molecular mechanisms by which disruption to mitochondrial reactive species and redox signalling networks contribute to acute pathologies and chronic degenerative disorders. This will help to develop new classes of rational therapies for these disorders.

Professor Rita Horvath

Newcastle University

Exploring novel molecular targets in mitochondrial protein synthesis to develop treatments in mitochondrial disease

Professor Karl Kadler

University of Manchester

What are the mechanisms by which cells establish and maintain collagen fibril-rich tissues?

Collagen is the most abundant structural protein in vertebrates. It occurs as centimetre-long fibrils in connective tissues such as skin, tendon, ligament, cartilage and blood vessels. A primary function of the fibrils is to 'stress shield' cells from the potentially damaging forces imposed on tissues by everyday activities like walking. A good analogy is the buildings in which we live and work – there are thousands of tons of concrete above our heads, but the walls protect us by a phenomenon called stress shielding. Collagen fibrils are made during early adulthood and last for our entire lives. This raises an important question about how cells protect the fibrils and if failure of a protective mechanism underlies chronic diseases such as tendinopathies, osteoarthritis and heart disease. Professor Kadler hypothesises that the circadian clock regulates the synthesis and removal of a mechano-protective matrix whose job it is to protect the precious collagen fibrils from being damaged by wear and tear. Using genetic manipulation, mechanical testing and by studying the protein secretory pathway in cells, Professor Kadler aims to understand the role of the circadian clock in tissue maintenance. The work could lead to new ways of preventing chronic diseases of tendons, ligaments, cartilage, skin and blood vessels.

Professor Achillefs Kapanidis

University of Oxford

Molecular mechanisms and regulation of bacterial transcription in vivo

Transcription is a fundamental process for all organisms, constituting the first step in gene expression, and controlling the ability of living systems to develop, differentiate, sense their environment and adapt. Tight regulation mechanisms are required to ensure that the correct genes are expressed at the correct time and place and at the levels required. The timing of transcription is controlled during transcription initiation; a complicated process with many transitions involving transient, dynamic complexes formed through protein and DNA conformational changes. Professor Kapanidis will use cutting-edge single molecule approaches to elucidate the molecular mechanisms that living cells employ to regulate the transcription of genes in a precise spatial and temporal manner by direct, real-time visualisation of transcription on single genes inside single living cells.

Professor James Kaufman

University of Cambridge

Comparative studies to understand the role of class II molecules expressed in epithelial cells

The major histocompatibility complex (MHC) encodes molecules that play crucial roles in the immune responses of vertebrates, including classical MHC class I and class II molecules presenting peptides from the inside of cells to T lymphocytes. Chickens have a much simpler MHC compared to mammals, which has allowed the discovery of phenomena that are difficult to discern in the more complex mammalian MHC, most recently the expression of particular MHC class II molecules primarily in epithelial cells of the chicken intestine. Such specific expression of class II molecules is unprecedented and particularly interesting as the intestine is filled with both beneficial commensal organisms and potential pathogens, and decisions about whether to mount an immune response are complex. Perhaps as a result, the intestine is a site of many infectious, autoimmune and inflammatory diseases. Professor Kaufman wishes to understand the mechanisms and functions associated with these novel class II molecules, first in chickens, and then in mammals.

Professor Paul Klenerman

University of Oxford

Function of novel human T-cell subsets in host defence

The immune system of the gut and the liver are finely tuned to respond rapidly to dangerous infections, but to tolerate normal commensals and food. Among the lymphocyte populations involved in such host defence in humans are newly defined subsets of T cells with unconventional functions. The focus of Professor Klenerman’s studies are two subsets of related CD8+ T cells which both express the cell surface receptor CD161, including a group of cells with antibacterial responsiveness designated mucosal-associated invariant T cells. The aim of this work is to define what the functionality of these cells is in normal tissues, and to what extent it may be modulated in infectious and inflammatory disease, including viral infections such as chronic hepatitis. Since these cell types are a dominant tissue-resident population, these studies look to define their role in normal host defence and in disease pathogenesis, offering routes for intervention.

Professor Peter Latham

University College London

Learning as Bayesian inference

Professor Matthias Marti

University of Glasgow

Elucidating mechanisms of extracellular vesicle-mediated cellular communication and stage conversion in malaria parasites

Malaria parasites cycle between an asexual proliferative and a sexual transmission stage during human infection. To enable efficient transmission to the mosquito, vector parasites need to finely tune the balance between asexual reproduction and sexual development. It has been demonstrated that extracellular vesicles can be transferred between parasite-infected red blood cells (iRBCs) and impact the rate of sexual stage activation, or sexual conversion rate. Professor Marti’s group will define the mechanistic basis of vesicle-mediated cellular communication between iRBCs and its link to the regulation of sexual stage formation. This work has the potential to generate new paradigms in our understanding of Plasmodium biology and interactions with the host environment, and possibly in related Apicomplexan parasites. Understanding the mechanistic basis for Plasmodium’s capability to communicate and regulate the rate of reproduction versus transmission also provides a powerful opportunity for novel interventions.

Professor Anthony Maxwell

John Innes Centre

Understanding and exploiting the role of type II DNA topoisomerases in DNA replication and recombination

DNA topoisomerases perform vital roles in all organisms, regulating DNA topology (supercoiling, catenation, knotting), during replication, recombination and transcription. These enzymes have also emerged as valuable drug targets for both antibiotics and anti-cancer drugs. Professor Maxwell will use structural, biochemical and biophysical approaches to further investigate the role of DNA topoisomerases in DNA replication and recombination, and to understand how the DNA cleavage/religation reaction is regulated in relation to cellular function. He will address long-standing questions in the field, such as the role of ATP hydrolysis in type II topoisomerase reactions, how type II topoisomerases carry out illegitimate replication, and the physiological role of topoisomerase VI in DNA replication.

Professor Thomas Meier

Imperial College London

Molecular mechanism of rotary ATPases and their role as new targets in infectious diseases

ATP is the universal energy storage molecule living cells use to power biochemical reactions. A human being needs approximately their own body weight of ATP per day. ATP is produced by the enzyme ATP synthase; it converts the energy stored in an electro-chemical gradient of protons or sodium ions into ATP and operates by a unique rotary mechanism. Professor Meier aims to understand the structure and operation principles of this molecular machine, and to decipher its mechanism using structural and biophysical methods, including cryo-EM and X-ray crystallography. Specifically, he will investigate how rotary ATPases dynamically couple ion translocation with ATP synthesis and how new types of drugs and inhibitors, such as the class of diarylquinolines, attack and inhibit rotary ATPases on a molecular level. 

Professor Conrad Nieduszynski

University of Oxford

How does a cell complete genome replication?

Accurate and complete genome replication is essential for all life. A single DNA replication error in a single cell division can give rise to genomic disorders, including cancer. Professor Nieduszynski’s research aims to determine how cells faithfully complete genome replication before cell division. Errors in DNA replication occur on single molecules in individual cells. However, these errors can be hidden from view in genomic approaches that look at data from populations of several million cells, causing the pattern of DNA replication in single cells to be hidden by the population average. Consequently, rare problems during DNA replication, including delays in completing replication, cannot currently be readily detected. During this award, Professor Nieduszynski will develop novel single-molecule methods to directly measure DNA replication in single molecules and determine the dynamics of genome replication at the DNA sequence level, and investigate the consequences of insufficient replication origin activity.

Professor Luke O'Neill

Trinity College Dublin

Metabolic reprogramming in innate immunity

Professor O’Neill will investigate metabolic changes occurring in macrophages upon activation of innate immune signalling pathways. Metabolic reprogramming of cells of the immune system has been the focus of recent work by immunologists, with complex alterations occurring in metabolic pathways that govern the function of the immune cell being activated. Specific metabolites accumulate, that then signal to gene expression programmes, enhancing immunity and inflammation. Firstly, the role of the metabolite succinate in generating reactive oxygen species from complex I in reverse electron transport will be investigated. Citrate accumulation leading to the production of malonyl-CoA and malonylation of the enzyme GAPDH will then be examined in detail. This process might lead to GAPDH dissociating from target mRNAs for critical inflammatory mediators, leading to enhanced translation. Finally, the role of glutathionylation and its regulation by the enzyme glutathione transferase omega will be further analysed, as this appears to be another determining event in macrophage activation. This project may point to new therapeutic approaches to limit macrophages in inflammatory and immune diseases.

Professor Tracy Palmer

University of Dundee

Identification of substrates and roles in virulence of the Staphylococcus aureus Ess protein secretion system

 

Professor Andreas Schaefer

University College London

Behavioural role and neural representation of temporal dynamics in sensory stimuli

The world is a dynamic place. This is particularly true for the sense of smell. Air turbulences impose a rich temporal structure onto smells, as can be appreciated from watching smoke meandering, for example. Professor Schaefer will explore what this temporal structure is, what information it contains, how it is represented in the brain and how it is used to extract critical insight about the world, such as the location of odour sources. Through electrical recordings, images of brain activity and perturbation of specific neuronal types, he will investigate how stimulus dynamics govern behaviour, and thus unravel mechanisms of how information about the external world is represented and processed in neural circuits.

Professor Peter Stockley and Professor Reidun Twarock

University of Leeds and University of York

New perspectives for antiviral therapy: the regulatory roles of genomic RNA in virus assembly, infection and evolution

 

Professor Guy Thwaites

Oxford University Clinical Research Unit, Vietnam

Personalised adjunctive anti-inflammatory therapy to reduce deaths from tuberculosis

Professor Daan van Aalten

University of Dundee

Mechanisms of O-GlcNAc signalling

Glycosylation of serines/threonines, with O-GlcNAc on nucleocytoplasmic proteins in higher eukaryotes, is an abundant and dynamic intracellular post-translational modification that is essential for metazoan life. Dysregulation of this O-GlcNAcylation has been linked to a diverse set of human diseases, including neurodegeneration, cancer and diabetes. While O-GlcNAc has been identified on over 1000 proteins, it’s not clear how only two enzymes, O-GlcNAc transferase and O-GlcNAcase, can produce this dynamic signalling system. Professor Van Aalten will use Drosophila as a model system to understand how the O-GlcNAc transferase recognises specific proteins as substrates. He is also planning to use a combination of crystallography and chemistry to identify the molecular mechanisms that underpin O-GlcNAc signalling.

Professors Graham Williams and J. H. Duncan Bassett

 

Imperial College London

Cellular thyroid hormone availability: regulation of development and tissue repair, and pathogenesis of degenerative disease

The basic cellular and molecular programmes that drive growth and development are also essential for tissue maintenance and response to injury. These fundamental mechanisms have been evolutionarily optimised for reproductive fitness, but not for healthy ageing. Dynamic regulation of intracellular thyroid hormone availability is an evolutionary conserved development switch that controls cell proliferation and differentiation, organ maturation and growth. Reversion to this critical developmental programme has recently been implicated in injury and tissue repair. During this award, Professors Williams and Bassett intend to provide a comprehensive understanding that can be exploited for therapeutic benefit in the prevention and treatment of degenerative disease and tissue injury. They have developed unique resources required to manipulate the developmental switch in a conditional and cell-specific manner. They hypothesise a fundamental role for regulated thyroid hormone availability in the coordination of tissue development and function, but its dysregulation in ageing and chronic disease.

Professors Anne Willis and Kathryn Lilley

 

University of Leicester and University of Cambridge

Transcription, Trafficking, Translation: dissecting the spatiotemporal mechanisms underlying localised protein synthesis

Proteins are central to all processes that take place inside cells and reside at defined intracellular locations tailored to their function. DNA in the nucleus is transcribed into mRNA that migrates from the nucleus into the cytoplasm, where it is translated into proteins, which are trafficked to the location in the cell where they are required to perform their defined function. Little is known about the spatial organisation of the translation of proteins that are synthesised in the cytosol, or peripherally-associated membrane proteins. Many diseases are known to be associated with protein mislocalisation. Professors Lilley and Willis will use their award to define the spatial relationship of the transcriptome, proteome, and the processes that control this relationship, by creating global subcellular maps of proteins and mRNA following specific cellular stimulation. They will combine genomic, proteomic, quantitative cell biological and biochemical approaches, in conjunction with large-scale informatics, and will develop new methodologies and pipelines to understand the control of localised protein synthesis globally.

 

July

Professor Benjamin Berks

University of Oxford
Moving folded proteins across membranes

All bacteria produce proteins that operate on the outside of the cell. To reach their correct location these proteins must be exported across the normally impermeable cell membrane by specific transporter systems. The twin arginine translocation (Tat) system is a protein exporter with the highly unusual ability to transport folded proteins. It is required for the virulence of many common pathogens. Tat transport involves the formation of a transient transporter complex. Professor Berks has recently identified ways of following the behaviour of the Tat transporter complex in real time in living cells, of stalling the transporter complex in the assembled state, and of solubilising the transporter complex from its native membrane environment. Professor Berks will exploit these advances to address fundamental questions about the structure and mechanism of the Tat apparatus.

Professor Sir Adrian Bird

University of Edinburgh
Towards understanding and treatment of MECP2-related disorders

Mutations in the MECP2 gene are responsible for two autism spectrum disorders: a loss of function causes Rett syndrome, while over-expression causes MECP2 duplication syndrome. As either too little or too much MECP2 protein leads to profound intellectual disability, understanding how this protein contributes to brain function is a priority. One hypothesis is that is that MECP2 is a multifunctional hub protein implicated in diverse cellular pathways, while a simpler alternative is that MECP2 is primarily a transcriptional repressor that binds methylated DNA and recruits a co-repressor complex. Professor Bird will investigate these hypotheses with experiments that will identify both the determinants of MECP2 binding to chromatin and how varying levels of MECP2 affect gene expression.

Professor Marina Botto

Imperial College London
Complement C1q and CD8+ T-cell immunity – implications for autoimmunity

Patients with the autoimmune condition systemic lupus erythematosus (SLE) develop antibodies that react with molecules found in all the cells of the body, known as autoantibodies. When autoantibodies bind to 'self' molecules, they may cause disease by inducing inflammation in the kidney, skin and other organs. A group of blood proteins called the complement system play a key role in preventing the development of SLE by facilitating the disposal of dying cells and regulating the immune response. During this award Professor Botto’s group will investigate whether and how the deficiency of one component of the complement system, C1q, alters the function of a specific type of immune cell (CD8+ T cells). Ultimately these studies will help to define a new molecular framework for addressing the role of virus infections as potential triggers of autoimmunity.

Professor Frances Brodsky

University College London
The physiological role of clathrin light-chain diversity in vertebrates

Clathrin-coated vesicles are responsible for cell-cell interactions in eukaryotic organisms by mediating membrane traffic pathways that control receptor expression and organelle formation. This process regulates cellular metabolism, cell growth, and immune and nerve cell function. Using cell biology, protein chemistry and mouse genetics, Professor Brodsky will investigate how the light-chain subunits of clathrin coat influence the physiological function of clathrin in vertebrates and how clathrin light-chain diversity enables tissue-specific clathrin functions.

Professor Clare Bryant

University of Cambridge
Inflammasome formation in infectious and inflammatory diseases

Upon infection or injury the host mounts an innate immune-driven inflammatory response to control infections and repair damaged tissue. Dysregulation of innate immunity, however, is associated with many diseases such as cardiovascular disease, diabetes, cancer and autoimmunity in humans and animals. Receptors present inside the cell (NOD-like receptors) sense bacteria and viruses, or non-infectious danger-associated molecules produced endogenously, to form a macromolecular inflammasome-signalling complex which drives protective immunity against pathogens and optimises the development of adaptive immunity. Professor Bryant’s research programme will investigate how inflammsome-signalling complexes self-assemble within cells in response to different pathogens or ligands and the consequent functional impact on the host immune response to infection. The impact of within- and between-species diversity in inflammasome genes on inflammasome self-assembly and host innate immune responses will also be investigated.

Professor George Christophides

Imperial College London

Anopheles-Plasmodium interactions: mosquito immune response and parasite immune evasion strategies

Professors Nicholas Franks and William Wisden

Imperial College London
Capturing the neuronal ensembles underlying sleep and sedation

Why we spend one third of our lives in a state of vulnerable inactivity – sleep – is an enduring mystery. Like hunger and thirst, the urge to sleep is a primal biological drive. It builds during waking and then dissipates during sleep. But the question of what exactly the drive to sleep is remains unsolved. In fact the drive to sleep after prolonged sleep deprivation seems so strong that it is similar to taking a sedative drug. During this award, Professors Franks and Wisden will investigate the mechanisms underlying the sleep drive and ask whether certain sedatives produce unconsciousness by activating the same neuronal pathways. Using a genetic approach that 'tags' the neurons involved, they aim to find out how these circuits function. A deeper knowledge of how sedatives work could lead to drugs that have fewer side effects and might even give the restorative benefits of natural sleep.

Dr Clare Jolly

University College London
Virus-host interactions regulating HIV-1 replication in T cells

To successfully infect human cells and cause AIDS, HIV must navigate a complex environment, hijacking the essential cellular machinery it needs to replicate and spread, while avoiding innate and adaptive immune defences. The aim of Dr Jolly’s research is to understand the molecular cell biology of HIV infection and how this shapes pathogenesis. HIV exploits direct cell-to-cell spread to rapidly disseminate at immune cell contacts. During this award, Dr Jolly will explore exactly how HIV co-opts cellular signalling pathways to drive successful infection and spread in T cells, and determine the biological consequences for the virus and the host. These studies seek to provide greater insight into virus infection of immune cells. This will advance understanding of HIV pathogenesis and contribute fundamental knowledge about T-cell function in health and disease, potentially informing future antiviral strategies.

Professor Kim Nasmyth

University of Oxford
How are chromosomes held together by cohesin?

Each chromosome must be replicated to produce sister DNAs, which segregate to opposite sides of the cell during mitosis. Chromosomes metamorphose into threads largely segregated from their sisters but attached along an inter-chromatid axis through sister chromatid cohesion. This ensures that sister DNAs are pulled in opposite directions. Professor Nasmyth has identified proteins that mediate sister chromatid cohesion and shown that they form a multi-subunit ring-shaped complex called cohesin. He has proposed that cohesin holds sister DNAs together by trapping them within its ring structure. Professor Nasmyth aims to establish the universality of this 'ring model' to elucidate how DNAs enter and exit cohesin. He will also apply insights derived from cohesin to understanding how a related complex called condensin holds the DNA within individual chromatids together. This work will enrich chromosome biology and yield insights into tumours and age-related infertility in females.

Professor Nicholas Proudfoot

University of Oxford
Molecular mechanism and regulatory function of protein coding gene transcriptional termination in mammalian genomes

The enormous facility with which mammalian genomes can be sequenced has outstripped our understanding of gene function in a genomic context. This disconnect between genomics and gene mechanism is especially evident in understanding how gene transcription units are defined. Professor Proudfoot investigates transcription termination – both its basic mechanism and how it acts to regulate gene output. He will combine genomic analysis of nascent transcription with mechanistic studies, and aims to define the class of termination mechanism for each gene in the human genome and understand why termination is defective in cancer. This information will be important to better understand how specific genes are regulated and could ultimately aid more effective cancer therapy.

Professor Daniel Raleigh

University College London
The molecular basis of islet amyloid induced beta-cell death and the inhibition of islet amyloid induced toxicity

Amyloid formation plays a central role in a wide range of devastating diseases such as Alzheimer's and Huntington's disease, but the mechanism of amyloid formation has yet to be defined in detail for any protein. The nature of the toxic species produced during amyloid formation is controversial and past efforts at drug development that target amyloid for therapeutic benefit have been disappointing. Professor Raleigh's work will focus on islet amyloidosis by the neuropancreatic hormone islet amyloid polypeptide and its role in type 2 diabetes and pancreatic beta-cell death. His lab is aiming to determine how islet amyloid polypeptide forms and why it forms both toxic and non-toxic oligomers.

Professors David Ray and Andrew Loudon

University of Manchester
Clock control of inflammation in the lung

Circadian rhythms dominate virtually all aspects of human physiology. It is now established that disruption of the circadian clock has a profound impact on inflammation in both humans and in animal models. During this award, Professors Loudon and Ray intend to address the fundamental question of how the clock controls host defence. To do this, they will focus on pulmonary inflammation and specifically aim to elucidate how time-keeping and inflammatory cells communicate to shape pulmonary immune response, how the molecular clocks control pro- and anti-inflammatory signalling within the lung, and how clock regulation of epigenetic structure mediates inflammatory set point. The aim of this award is to further our understanding of how local tissue environment and the immune system interact to dictate the magnitude, direction and responsiveness to treatment at sites of immune challenge.

Professor Angela Roberts

University of Cambridge
Fractionating the functions of primate ventromedial prefrontal cortex of relevance to depression

Depression has a lifetime prevalence of 16 per cent and is the single most important contributor to the total European disease burden. Unfortunately, the current range of treatments is relatively restricted and their success is limited and variable because of the marked individual differences in symptoms and the varied reasons why someone may become depressed. Depressed patients have marked changes in activity in a brain area called the ventromedial prefrontal cortex, but whether these alterations are a cause of depression or a compensatory change is unclear. Thus, the goal of Professor Roberts's research is to identify the different functions of distinct regions within the ventromedial prefrontal cortex and associated brain circuitry and determine how they relate to different symptoms of depression, and how they are modulated by existing drug therapies. Not only will this allow existing therapies to be targeted more effectively, but it will also help discover new therapies and guide personalised treatment strategies.

Professor Philippe Schyns

University of Glasgow
Brain algorithmics: reverse engineering dynamic information processing in brain networks from MEG time series

The ultimate goal of cognitive neuroscience is to understand the brain as an organ of information processing. This will remain difficult unless we understand more directly what information the brain processes when it categorises the external world. For example, our brain can extract from a face (a powerful social communication tool) information to categorise identity, age, gender, ethnicity, emotion, personality and even health. Though our brain knows what information to use for each task, as information receivers we typically do not have direct access to this knowledge. The current state of cognitive neuroscience is similar – we aim to understand the brain as an information processor, but we do not know what stimulus information it processes. Professor Schyns will address this fundamental problem by developing brain algorithmics, a framework that first isolates what specific information underlies a given face categorisation, then examines where, when and how the brain processes this information.

Dr Christian Speck

Imperial College London
Assembly, function and molecular architecture of the eukaryotic replicative helicase

Perhaps the most fundamental property of all living things is the ability to replicate their DNA, which allows cells to pass on their genetic material from parent to progeny. Accurate DNA replication is essential for genomic stability and organismal wellbeing. Errors in DNA replication are strongly associated with ageing and cancer. The ring-shaped replicative helicase complex MCM2-7 plays a vital role in DNA replication. Dr Speck is investigating the molecular basis of MCM2-7 ring opening using structural, genetic and biochemical techniques to understand how this fundamental molecular machine functions during DNA replication. Understanding the underlying mechanism of how the replicative helicase gains access to DNA, is regulated on DNA and is released from DNA will also aid the development of novel DNA replication inhibitors with therapeutic value.

Dr Jonathan Stoye and Dr Ian Taylor

The Francis Crick Institute
Lentiviral accessory proteins Vpx and Vpr, viral countermeasures to host cell defences

Vpr and Vpx are essential lentiviral accessory proteins required for optimal infection of immune cells by HIV-1 and HIV-2, the causative agents of AIDS. The function of Vpr and Vpx is to implement the destruction of host-cell defence proteins that would otherwise inhibit virus replication and so render the host permissive to infection. Both Vpx and Vpr exert their effects through interaction with DCAF1, a host-cell adaptor protein that directs proteins to the cell's E3 ligase ubiquitination machinery. Using their combined strengths in structural biology, retrovirology and cell biology, Dr Stoye and Dr Taylor propose to investigate how Vpx and Vpr interact with their cellular targets and examine the consequences for HIV-1 infection upon modification or disruption of these interactions. Such studies are prerequisites to the development of drug molecule ‘disruptors’ of this host-pathogen interaction that target viral countermeasures and expose the virus to the full effects of cellular defences.

Dr Brian Stramer

King's College London
Dissecting the cellular mechanics of contact inhibition of locomotion

Contact inhibition of locomotion (CIL), a process whereby migrating cells collide and repel each other, is critical during embryogenesis and is hypothesised to play a role in pathologies such as cancer. This phenomenon can be observed in vivo during the dispersal of embryonic Drosophila immune cells (macrophages), which require CIL for their developmental migrations in living embryos. The precise patterning of macrophage movement in Drosophila embryos is controlled by CIL. Dr Stramer aims to elucidate both the molecular and mechanical mechanisms regulating this process by exploiting a wide array of techniques available in this model system, such as live imaging and genetic manipulation.Knowledge and analytical techniques developed from these studies will be extrapolated to mammalian models of immune cell interactions to investigate the wider role of CIL in animal physiology.

Dr Nicolas Tapon

The Francis Crick Institute
Tissue growth control and mechanics during development

How each cell in a developing animal ‘knows’ to stop growing and dividing when the correct body size and shape has been reached is of fundamental importance to our understanding of diseases such as cancer. Systemic cues acting at the organism level, such as nutrient availability, strongly influence final organ size, as do signalling molecules involved in patterning, which couple tissue growth control with pattern formation. Recently, it has been shown that as the tissue grows, changes in physical forces might act as a developmental timer that specifies the onset of growth arrest. The conserved Hippo pathway, discovered in Drosophila genetic screens for tumour suppressors, is a good candidate to mediate the effect of mechanical forces on size control. Dr Tapon will investigate when and how the Hippo pathway is regulated during development and the mechanisms by which the cellular mechanical environment influences developmental growth arrest via Hippo signalling.

Professor Philip Taylor

Cardiff University

Understanding the molecular controls of tissue resident macrophages

Dr Steven West

University of Sheffield
Control, specificity and function of RNA polymerase II modification in human messenger RNA maturation

Messenger RNA (mRNA) processing by capping, splicing and cleavage and polyadenylation generates protein-coding information from primary transcripts. The maturation of mRNA is coordinated with transcription via phosphorylation of the C-terminal domain of the large subunit of RNA polymerase II. This modification is thought to constitute a code that orchestrates transcriptional and mRNA maturation events. Dr West will make use of a combination of biochemistry, genome editing and proteomics in order to investigate both how this C-terminal domain modification is co-transcriptionally regulated and whether there are other interacting proteins that are essential for the biological effects of this phosphorylation.

April

Professor Judith Allen

University of Edinburgh
Chitinase-like proteins: host protection through molecular multi-tasking

Helminth infection results in a host-protective type 2 immune response that is important for both parasite control and tissue repair. Chitinase-like proteins (CLPs) are induced during type 2 immunity, and are strongly associated with helminth infection, tissue injury and a variety of chronic diseases. CLPs unexpectedly induce the pro-inflammatory cytokine IL-17, leading to a response that limits parasite numbers but at a cost of enhanced tissue injury. As infection progresses, CLPs contribute both to the induction of a protective type 2 immune response and to repair of the damaged tissue. Professor Allen will use a tissue-migrating helminth model to investigate how CLPs perform such diverse tasks and reveal why they are so strongly associated with numerous pathological conditions. More fundamentally, the studies will provide key insight into how IL-17 pushes the type 2 response into a more pathological state, which will be relevant to a range of chronic conditions.

Professor Peter Brophy

University of Edinburgh
Identifying how membrane proteins required for saltatory conduction are trafficked and stabilised in PNS axonal domains

Rapid nerve impulse conduction in vertebrate nerves depends on the clustering of voltage-gated sodium channels at nodes of Ranvier, which are gaps between the successive myelinated segments of axons. If nerves lose their myelin sheath, such as in multiple sclerosis or Charcot-Marie-Tooth disease, nodes are disrupted, leading to loss of nervous system function, blindness, paralysis or even death. Professor Brophy’s team have discovered that a protein called neurofascin plays an essential role in clustering these channel proteins at nodes in response to myelination, but there is currently little understanding of how it does this. The objective during this award is to directly visualise how neurofascin accomplishes this crucial task by using conventional and super-resolution light microscopy to track the targeting and fate of fluorescently-tagged nodal proteins in living nerves. This information will then be used to probe the mechanisms of node assembly and stabilisation.

Professor Andres Floto

University of Cambridge
The host response to Staphylococcus aureus infection

Professor Floto's team are focused on understanding how the innate immune system interacts with Staphylococcus aureus. Specifically, they will examine how this bacterium can disrupt macrophage function to avoid intracellular killing, how autophagy is activated and may be subverted, and how cellular invasion is sensed and signalled to the wider immune system. They are particularly interested in how signalling through nerve growth factor beta coordinates effector immune responses during infection and may potentially be therapeutically stimulated to enhance bacterial clearance.

Professor Gad Frankel

Imperial College London
Deconstructing Citrobacter rodentium pathogenesis

The control of bacterial infections is arguably the most important achievement of modern medicine. However, the rapid emergence and spread of antibiotic resistance emphasises the constant need to develop new antimicrobial therapies and vaccines. The development of effective control measures requires a systematic understanding of the biology of the disease in the context of the complex interactions between bacterial pathogens and their hosts. The human intestinal pathogens enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) use a type III secretion system to inject effectors into infected cells, where they reprogram cell signalling. The global aim of this project is to study the function of the effectors, including the identification of their partner proteins in infected enterocytes, in vivo. The programme will focus on Citrobacter rodentium as a well-established and tractable murine system that serves as the model to study EPEC and EHEC pathogenesis and mucosal immune responses to infection.

Dr Elena Gheorghiu

University of Stirling
Towards a better understanding of mirror-symmetry coding in human vision

Mirror symmetry is a ubiquitous feature in natural images, in both biological and man-made objects. Symmetry provides insight into the ways in which human vision solves fundamental perceptual problems. It plays an important role in object recognition and figure-ground segmentation. During this award, Dr Gheorghiu will investigate neural mechanisms responsible for mirror-symmetry perception in human vision with the aim of elucidating how these mechanisms interact with those involved in colour, stereoscopic depth and motion processing. She will use a combination of approaches: appearance-based and performance-based psychophysical methods, event-related potential methods, and computational modelling. This research programme will advance our understanding of how mirror-symmetry mechanisms operate in individuals with normal vision and will provide insight into the spatiotemporal flexibility and limitations of these mechanisms. A better understanding of mirror-symmetry coding in human vision will enable the prediction of how these mechanisms will be affected in an ageing visual system and in individuals with abnormal processing of mirror-symmetric form.

Professor Jonathan Higgins

Newcastle University
The function of histone modifications in mitosis

For productive division, cells must accurately segregate their chromosomes and pass lineage-specific gene expression patterns to their daughters. These events involve the recruitment to chromatin of proteins required for chromosome segregation, the displacement of transcription factors to downregulate or reprogram transcription, and the retention of specific bookmarks that allow memory of the transcription program to be inherited through mitosis. Histone modifications, which regulate the association and dissociation of mitotic regulators and transcription factors from chromosomes, are critical for these events. Professor Higgins will address fundamental questions that remain about these mechanisms of regulation during cell division.

Professor Jay Hinton

University of Liverpool
Novel virulence properties of non-typhoidal Salmonella associated with epidemics in bloodstream infection

Invasive non-typhoidal Salmonella disease is causing a global epidemic of bloodstream infection. Salmonella bacteria are targeting HIV-infected adults and immune-suppressed children, killing 388,000 people each year across Sub-Saharan Africa. Although the clinical picture is well established, there has been a lack of basic research into this neglected disease. Professor Hinton’s research will identify the specific properties of the new types of Salmonella that are responsible for the African clinical syndrome. Using a multidisciplinary approach involving functional genomics and comparative transcriptomics, this project will contribute to our understanding of the evolution of virulence in bacterial pathogens.

Dr Peter Lawrence

University of Cambridge
Novel approaches to the cell biology of planar cell polarity

Cells in epithelial sheets are polarised in the plane of the sheet, as shown by the patterned orientation of mammalian hairs and insect bristles. This fundamental phenomenon, known as planar cell polarity (PCP), is essential during development, and failures in PCP have been implicated in common human birth defects, such as cleft palate, spina bifida, hearing defects and polycystic kidney disease. Dr Lawrence studies PCP in the fruit fly Drosophila and has recently discovered that single epithelial cells can be multipolar - polarised in different directions - suggesting that the mechanisms of PCP are subcellular. During this award, Dr Lawrence aims to understand the molecular mechanisms by which cells read and interpret their environment to determine their orientation and communicate this information to neighbouring cells, by using a combination of Drosophila genetics, cell biology and in vivo imaging.

Professor Boris Lenhard and Professor Ferenc Mueller

Imperial College London and University of Birmingham
The core promoter: an unexplored regulatory level of transcription during vertebrate development

Critical transitions in animal development are determined by a succession of transcriptional regulatory events mediated by a large number of cis-regulatory modules, which are integrated into transcription initiation at RNA polymerase II core promoters – the DNA sequences at which transcription to RNA is initiated. The type of the core promoter is the regulatory point that critically determines the activity profiles of genes. However, different types of promoters are defined tentatively, and the role of the differences is often overlooked. The principal reason for this is our current lack of understanding of promoter regulatory codes and their functional diversity, which can provide key insights into their underlying biology. Professors Lenhard and Mueller are planning to address this issue by investigating the systematic use of distinct promoter types for specific regulatory purposes, to discover unknown classes and subclasses genome-wide, define their fundamental properties, and uncover their functions in regulating transcription in the developing embryo.

Professor Bradley Love

University College London
Neural and computational mechanisms of categorisation

Judging a person as a friend or foe, or a tumour as cancerous or benign are examples of categorisation tasks. Category knowledge provides a necessary basis for almost every cognitive act, ranging from assessing the value of an object to problem solving. This project evaluates a novel theory about how people learn and use category information to make critical decisions. The theory emphasises how people sample their external world (e.g. eye movements) and their internal world (e.g. memory retrieval) when learning and making decisions. A computer model is used to simulate how people learn and categorise novel objects. The psychological and neural plausibility of this model will be evaluated in a series of brain-imaging studies. The outcomes of this project should inform best practices for treating people who have difficulties in the mental processes supporting categorisation, including those related to learning, memory retrieval and attention.

Dr Goedele Maertens

Imperial College London
Characterisation of a novel human T-cell lymphotropic virus integrase binding partner: from structure to function

The delta-retrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the cause of an aggressive T-cell leukaemia and a debilitating neurological disease. To date, there are no effective treatments. One unique and essential step in the life cycle of retroviruses such as HTLV-1 is the integration of a DNA copy of the viral RNA into the host genome. This process is catalysed by the viral enzyme integrase. Target site selection is not random, but appears to be determined by the interaction between integrase and a host factor. Recent findings suggest a correlation between integration into active transcription units, increased proviral expression and development of disease. Using a proteomics screen Dr Maertens's group has identified a set of HTLV-1 integrase binding partners, of which one candidate also significantly stimulates the HTLV-1 integrase biologically relevant activity. During this award the group’s main aims are to define the mechanism for modulation of IN activity by this novel host factor, to characterise the role of the integrase binding partners in HTLV-1 infection, and to structurally characterise the delta-retroviral integration machinery. This study will also inform the design and development of drugs to treat HTLV-1-infected patients.

Professor Gero Miesenboeck

University of Oxford
Time to decide

Many behaviours, including movement, navigation, communication and decision making, unfold over time. These behaviours must therefore be based on orderly sequences of nerve cell activity. How the brain generates such sequences is largely unknown. Professor Miesenboeck will explore this fundamental problem in fruit flies, which (like humans and higher animals) take time before committing to a choice. The amount of time taken varies with the difficulty of the decision and is heavily influenced by a small group of approximately 200 nerve cells in the fly’s central brain. These 200 cells are distinguished by the presence of FoxP, a genetic regulator molecule whose human versions are important determinants of cognitive ability. Professor Miesenboeck’s group will study how the activity of the FoxP-containing nerve cells in the fly changes as a decision progresses toward commitment, identify the biophysical principles and neuronal connections that support these evolving activity patterns, and investigate the molecular and cellular mechanisms through which FoxP acts.

Professor Chris Ponting

University of Oxford
CEROX-miRNA control of mitochondrial OXPHOS activities in health and disease

Low mitochondrial enzymatic activity is a shared feature of many neurological disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington’s disease and certain forms of brain cancer. Professor Ponting aims to explore the role of long non-coding RNA and micro-RNA in mitochondrial enzymatic activity, and will focus on a novel class of RNAs, termed competitive endogenous RNAs, which he has shown to affect oxidative phosphorylation. A diverse range of experimental and computational approaches will be used, as well as newly generated animal models. The ultimate goal is to ameliorate oxidative stress in iPS cell lines from patients with a variety of neurodegenerative or neuropsychiatric diseases including Alzheimer's and Parkinson's.

Dr Caetano Reis e Sousa

The Francis Crick Institute
Actin exposure as a universal trigger of inflammation

Inflammation is a response to microbial invasion or tissue damage designed to eliminate the offending stimulus, clear debris and stimulate tissue repair. Although much is known about the pathways that trigger inflammation in response to pathogen invasion, the induction of sterile inflammation following tissue injury remains poorly understood. This is an important area because dysregulated and/or chronic inflammation, often of sterile origin, is increasingly recognised to be a contributing factor to a vast range of human diseases, from cancer to neurodegeneration. During this award Dr Reis e Sousa will explore whether exposure of the actin cytoskeleton following cell damage contributes to sterile inflammation across species, and will investigate underlying mechanisms.

Professor Giampietro Schiavo

University College London
The mechanism controlling sorting and axonal retrograde transport in neurons

Neurodegenerative diseases carry a significant global health burden and are currently incurable. We have only incomplete knowledge about their pathological mechanisms and which physiological processes are key for disease onset and progression. Professor Schiavo's findings indicate that long-range transport pathways, such as fast axonal transport, are essential for maintenance and survival of neurons. Accordingly, deficits in axonal transport are associated with the onset of several neurodegenerative diseases, suggesting a causal role for dysfunctions in this pathway in these pathologies. Given the limited knowledge of the mechanisms controlling long-range axonal transport, the goal during this award is to address the mechanisms controlling the progression of cellular organelles along the axonal transport route. Professor Schiavo's lab will pursue this aim by investigating the journey of tetanus toxin, a potent neurotoxin causing tetanus in humans and animals, into the nervous system, and the role of components of its receptor complex in axonal transport and neuronal survival.

Professor Claudio Stern

University College London
Mechanisms that position the embryonic axis and the causes of identical twins

In humans, identical (as well as conjoined) twins can arise by spontaneous splitting of the embryo relatively late in development, right up to the time when the primitive streak forms, when the embryo already contains many cells. This suggests that the mechanisms that determine the position of the embryonic axis remain plastic for a long time, and that in normal development something must inhibit formation of multiple embryos. Almost nothing is known about the mechanisms involved in this embryonic regulation, which is likely to be responsible for the generation of monozygotic and conjoined twins in humans and other amniotes. Professor Stern plans to take a multidisciplinary approach, using chick embryos and the genetics of human populations systematically to identify inducers and inhibitors of axis formation and generate a comprehensive model of the cell and gene interactions controlling polarity, regulation and twinning.

Professor Rajesh Thakker

University of Oxford
Calcium-sensing receptor – a G-protein-coupled receptor – signalling pathways in health and disease

The calcium-sensing receptor (CaSR), a G-protein-coupled receptor that is widely expressed, is critical for calcium homeostasis and also has non-calcitropic roles (development of neurons and lungs, cell fate, tumorigenesis and gastro-entero-pancreatic physiology). Mutations of the CaSR and associated proteins cause approximately 75 per cent of hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, and CaSR abnormalities may also affect glucose homeostasis. However, precise molecular mechanisms of CaSR signalling and trafficking, and their calcitropic and non-calcitropic roles, remain to be elucidated. During this award, Professor Thakker aims to characterise CaSR signalling and trafficking pathways and facilitate translational research. These studies also aim to provide diagnostic and therapeutic advances for patients with calcitropic disorders (eg renal and metabolic diseases associated with kidney stones) and non-calcitropic disorders (eg diabetes mellitus).

Professor Brian Walker

University of Edinburgh
Tissue-specific control of cortisol versus corticosterone in humans

Human adrenal glands secrete both cortisol and corticosterone. High cortisol levels in blood cause Cushing's syndrome, with obesity and accelerated cardiovascular disease, while low levels cause Addison's disease. Professor Walker's research has shown that cardiometabolic risk factors in the population are associated with more subtle elevation in cortisol levels in both blood and tissue. However, any contribution of corticosterone in humans has been neglected to date. During this award, using the experimental medicine toolkit that his group has developed to study steroid physiology in vivo in humans, Professor Walker will extend recent discoveries that blood and tissue levels of cortisol and corticosterone are controlled independently, and establish the consequences for steroid signalling in adipose tissue in obesity. The programme will include proof of concept for a new therapeutic approach to improve metabolic control in patients with adrenal insufficiency.

2014

December

Dr Tal Arnon

University of Oxford

Regulation of splenic B-cell responses by tissue resident macrophages

The spleen provides a critical immune defence against pathogens that have reached the blood recirculation. Dr Arnon will study how immune responses are organised within the spleen, focusing on the roles of tissue-resident macrophages in regulating B-cell migration and activation. This research will use a combination of approaches, including novel mouse models and advanced imaging techniques, to determine the functional specification of distinct macrophage populations, and to define their roles in regulating humoral immune responses. These studies will advance our understanding of immunity against blood-borne antigens and the way by which tissue macrophages have evolved to address the specific requirements of their niche.

Professors David Baker and Michael Blackman

London School of Hygiene and Tropical Medicine and The Francis Crick Institute

Functional analysis of the cGMP signalling pathway in malaria parasites: a master regulator of life-cycle progression

Cyclic GMP (cGMP) is an intracellular messenger molecule that plays important roles in most cell types. Levels of cGMP in the cell are controlled by the opposing action of two enzymes called guanylyl cyclases and phosphodiesterases. When an environmental signal triggers this pathway, it brings about intracellular changes, often via the activation of a cGMP-dependent protein kinase. The cGMP signalling pathway has numerous roles in mammals, including perception of light by the eye, smooth muscle contraction, and heart function. The malaria parasite, Plasmodium, also has a functional cGMP signalling pathway which has been shown in recent years to regulate several important events during its life cycle in both the human host and mosquito vector. Professors Blackman and Baker will investigate the function and regulation of the pathway using biochemical and genetic approaches. Significant differences between the parasite and mammalian systems will present opportunities to develop novel antimalarial drugs.

Professor Imre Berger

University of Bristol

Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription

An essential first step in biogenesis is gene transcription. In humans, this process is regulated by complexes often comprising ten or more subunits, which arrange in superstructures that cooperate at the interface of chromatin, fine-tuned by activating and repressing modalities. Professor Berger's research aims to understand the cellular mechanisms of these protein machines, their assembly process from gene to functional complex, their interdependence in gene regulation and the factors that control them. He will study an archetypal general transcription factor complex (TFIID), a multiprotein coactivator (SAGA) and a multiprotein corepressor (NuRD), using a combination of macromolecular crystallography, electron microscopy, proteomics, cell biology and genetics.

Dr John Diffley

The Francis Crick Institute

How the eukaryotic replicative DNA helicase is loaded and activated

We each synthesise roughly 500 million km of DNA every day – more than the distance from the earth to the sun and back. Despite this scale, and the large number of tumour suppressor genes and potential oncogenes in our genomes, two-thirds of the UK population will live cancer-free lives. Thus, DNA replication and the quality control mechanisms associated with it are remarkably efficient. Dr Diffley is investigating how the minichromosome maintenance helicase is loaded onto replication origins and subsequently activated no more than once per cell cycle. Gaining a detailed understanding of how DNA replication initiates will help us to understand how high-fidelity DNA replication is ensured in normal cells, and is a prerequisite for understanding and exploiting the subversion of this process to potentially treat cancer.

Professor Changjiang Dong

University of East Anglia

From structural and functional studies of essential and novel lipopolysaccharide transport and assembly membrane proteins to novel drug discoveries combating emerging multidrug-resistant pathogenic bacteria

Antibiotics are the most successful medicines for controlling bacterial infections. However, bacteria adopt different mechanisms to gain drug resistance, which is becoming a huge global health problem. Multidrug-resistant Gram-negative bacterial infections are more difficult to control than those of Gram-positive bacteria, as the Gram-negative bacteria have an additional membrane, the outer membrane, protecting the bacteria from the antibiotics. Lipopolysaccharide is a main component of the outer membrane of Gram-negative bacteria, and is essential for the vitality of most Gram-negative bacteria and plays an essential role in drug resistance. Professor Dong will be using multidisciplinary approaches to investigate the molecular mechanisms of how membrane protein complexes of Gram-negative bacteria build up the outer membrane, with the goal of the development of novel antibiotics against multidrug-resistant bacterial infections.

Dr Shah Faruque

International Centre for Diarrhoeal Disease Research, Bangladesh

Multidisciplinary studies in the ecology and epidemiology of cholera to predict epidemics

Epidemics of cholera due to toxigenic strains of the bacterium Vibrio cholerae cause approximately 120,000 deaths and millions of cases annually, with major economic impact in developing countries. The pathogen naturally exists in an aquatic ecosystem and infects humans to cause the devastating diarrhoeal disease. The proposed research will involve a multidisciplinary approach to better understand the ecological interactions, epidemiology, and the intricate genetic regulations that allow the pathogen to survive under both environmental and host conditions, and factors which lead to periodic outbreaks of cholera. Dr Faruque has an outstanding track record of research in the ecology, epidemiology and evolution of V. cholerae and its bacteriophages. The planned studies using cholera as a model system are expected to provide important thematic insights which may be useful, not only in controlling cholera, but subsequently in a variety of other waterborne enteric diseases which affect populations in developing countries.

Professor Russell Foster

University of Oxford

The melanopsin signalling pathway in ocular, circadian and sleep physiology: mechanisms to clinical application

A major focus of Professor Foster's research has been to understand how light influences circadian rhythms – the daily cycle of biological processes that impact upon sleep and wakefulness. He is particularly interested in how photoreceptors in retinal ganglion cells of the eye detect and signal light information to regulate circadian rhythms. During this award, Professor Foster will use animal models to elucidate the neurobiological machinery that sets, maintains and tunes the internal clocks of mammals. He will also develop new pharmacological agents to adjust circadian rhythms in human subjects with abnormal sleep/wake timing. This work will significantly increase our understanding of the cellular and molecular determinants of sleep and wakefulness, while applying this knowledge to the task of improving human health across a broad range of conditions from eye disease to mental illness.

Professor Stephen F Goodwin

University of Oxford

Genetic dissection of sexual behaviour

Professor Goodwin uses the fruit fly, Drosophila melanogaster, to study the genetic determinants of sex-specific neural circuits and behaviours. He is particularly interested in the transcription factors fruitless and doublesex, which act together to specify and configure the anatomy and physiology of sex-specific neural circuitry. During this award, Professor Goodwin will use cutting-edge genetic, molecular and behavioural techniques to determine the principles that govern how fruitless and doublesex direct the assembly of neural circuits. He also plans to elucidate the neural circuits in the fly that encode sex-specific behaviours such as their distinctive courtship ritual. The research will significantly increase our understanding of how 'maleness' and 'femaleness' develop.

Dr Francois Guillemot

The Francis Crick Institute

Regulation of adult hippocampal stem cells by niche signals

Hippocampal stem-cell activity decreases with age, contributing to the degradation of spatial memory and affective behaviours in older rodents. New neurons are also added to the hippocampus in adult humans and these adult-born neurons are thought to contribute to hippocampal functions. It is thought that a reduction in stem-cell activity might therefore contribute to the cognitive impairments associated with human ageing, neurodegenerative pathologies and mood disorders. Dr Guillemot aims to better understand the mechanisms responsible for the vulnerability of these adult hippocampal stem cells to pathologies and old age, and in particular whether different subsets of stem cells are differentially affected by ageing. Better understanding of these mechanisms will serve as a foundation for further research into treatments against cognitive decline in patients and will also help develop strategies to improve the capacity of the brain to self-repair.

Professor Adrian Hayday

King's College London

Intraepithelial lymphocytes: lessons in immunoregulation from 'landlocked' T cells

During his award Professor Hayday will seek to update the current 'textbook' definition of the roles and actions of T cells. This research will place new emphasis on the fact that many tissues are constitutively replete with 'landlocked' T cells that Professor Hayday's laboratory has shown to respond very rapidly to tissue perturbation by infection and/or non-microbial stress such as physico-chemical insults. Pursuing the observation that the composition of the T-cell compartments differs from one anatomical site to another, Professor Hayday's hypothesis is that there are organ-specific epithelial molecules that ‘select for’ their cognate T-cell compartments. In support of this, the research group has identified a novel molecule, Skint1, expressed uniquely in thymic epithelium and in epidermal keratinocytes, that is required specifically for the development of the epidermal skin T-cell compartment. This research will test whether this is a generalisable phenomenon by tracking the identity of novel intestinal epithelial determinants of the gut T-cell repertoire. Such molecules may offer new insight into gut inflammation and interactions with the microbiome, and set a foundation for understanding T-cell compartments at other body surfaces.

Professor Glyn Humphreys

University of Oxford

I-brain: a neuropsychological analysis of social attention and cognitive control

Professor Humphreys is a cognitive neuropsychologist who performs basic and translational research on the relationship between attention and action as well as perceptual and social saliency. He uses lesion-symptom mapping to understand the neural substrates of neuropsychological disorders and to develop efficient screening tools for the assessment of cognitive deficits after brain lesions. During his award, Professor Humphreys will map the complex relationship between brain lesions and social-cognitive deficits in stroke and dementia patients. The research aims to reveal the neural basis of social cognition while addressing the important problem of whether deficits in social cognition due to brain damage can be identified and reversed with rehabilitation.

Professor Arthur Kaser

University of Cambridge

Can gene-environment interaction in Paneth cells trigger Crohn's disease?

Crohn's disease is a debilitating disease diagnosed at two peaks of age – in early adulthood, and in the sixth to seventh decade of life. It causes profound, life-long suffering and remains a major unmet medical need. Amongst immune-related diseases, Crohn's disease is special in that very few risk genes account for a huge fraction of its heritability. During his award, Professor Kaser will test the hypothesis that a genetically affected, relatively coherent biological mechanism operative in Paneth cells might determine the characteristic features of Crohn's disease involving the ileum. This mechanism would interact with more 'generic' genetically affected pathways, associated with increased immune reactivity and/or decreased tolerance, shared with other immune diseases. Delineation of such a mechanism will allow the predicting and testing of which environmental triggers set off ileal Crohn’s disease in genetically susceptible individuals. Together with studies in genetically stratified patient samples, Professor Kaser believes this affords an unparalleled opportunity to gain fundamental insights into Crohn’s disease, with the aim of informing a precise therapeutic intervention.

Professor Richard Maizels

University of Edinburgh

Helminths and the immune system: regulation, regulators and immunity

Helminths are intestinal and tissue parasites which have evolved sophisticated means of blocking the host immune system. Even today they infect over two billion people around the globe, but as yet no vaccines are available. Helminths are also associated with down-regulating 'bystander' reactions such as allergies, and other inflammatory diseases associated with modern lifestyles. By taking a molecular approach, Professor Maizels is identifying individual products from helminths which are able to suppress these inflammatory diseases, as potential new 'drugs from bugs'. Such defined molecules may offer the immuno-regulatory benefits of helminths while causing none of the harm of live infections. This research will also design new ways of building host immunity against infection, using these same molecules as targets for vaccines, and defining how to stimulate key types of immune-system cells to eliminate the parasites.

Professor Michael Malim

King's College London

Interferon and MX2-mediated control of HIV-1

Human cells are laden with genes and proteins that have evolved to inhibit viral infections. Many of these are rapidly mobilised in direct response to viral exposure and can collectively be called the mediators of innate immunity. The effectiveness of these fast-acting innate factors and mechanisms, together with later-developing adaptive immune responses, as well as the capacity of a virus to evade or counteract immunity, determines the outcome of infection in terms of health or disease, resolution or persistence. Professor Malim's research team will seek to discover innate immune mechanisms and pathways that can control infection by HIV, the virus that causes AIDS, and to define and understand the molecular underpinnings of viral suppression and evasion. This information can be leveraged in the future to develop or improve antiretroviral therapies, HIV vaccination strategies, and, potentially, approaches for HIV cure.

Professor Andrew McAinsh

University of Warwick

Kinetochores as force-sensing and -generating machines

During mitosis chromosomes undergo an exquisite series of four-dimensional manoeuvres that result in each daughter cell receiving an exact complement of the genetic material. At the heart of this process lie kinetochores, which assemble on each chromosome and form dynamic connections to spindle microtubules. There is an extensive parts list for the kinetochore, but we still lack an understanding of how the kinetochore moves and makes force. Professor McAinsh's research aims to understand the mechanisms by which kinetochore-microtubule complexes work as multi-component force-generating machines: how specific protein modules within the kinetochore complex collaborate to generate, exert and sense force. To achieve this, Professor McAinsh will be combining new microscope-based live-cell imaging assays with computational and biophysical tools. This work will provide key insight into how cells avoid errors in chromosome segregation, an event associated with developmental syndromes and cancer.

Professor Brian McStay

NUI Galway

The genomic architecture of human nucleolar organiser regions and its role in nucleolar biology

The nucleolus is the largest nuclear body and its primary role is ribosomal synthesis and assembly, though it also contributes to the cellular response to stress. The human genome contains approximately 300 ribosomal gene repeats, which are organised in tandem arrays at nucleolar organiser regions situated on the short p-arms of each of the five human acrocentric chromosomes. Professor McStay's research aims to determine how nucleolar organiser regions are arranged at a chromosomal level, how they direct formation of the nucleolus and how they regulate the function of nucleoli in human cells. He also plans to extend our understanding of the genomic architecture of the short arms of acrocentric chromosomes, as they are absent from the current human genome assembly.

Professor Shona Murphy

University of Oxford

The point of no return: a novel poly(A)-associated elongation checkpoint controlling gene expression

Professor Murphy aims to investigate a potential CDK9-regulated transcription-elongation checkpoint that is associated with polyadenylation signals at the end of protein-coding genes. This functions in addition to the well-known CDK9-dependent early-elongation checkpoint at the beginning of genes, and the failure of RNA polymerase II to negotiate this polyadenylation-associated checkpoint aborts transcription elongation prematurely. This checkpoint may provide a final quality-control step for mRNAs at the point of no return, after which a potentially functional mRNA is produced. Polyadenylation-associated checkpoints could therefore provide a powerful and rapid mechanism for the control of transcription in response to a range of signals, such as during development, where synchronous activation and repression of gene expression is required.

Professor Dónal O'Carroll

MRC Centre for Regenerative Medicine, University of Edinburgh

RNA regulation and modification in tissue development and homeostasis

The regulation of genomic output is of fundamental importance in the coordination of the complex processes that underpin stem-cell function and cellular differentiation essential for tissue development and homeostasis. Furthermore, understanding of the molecular mechanisms by which RNA modification and RBPs regulate gene expression is directly relevant to the comprehension of basic biological processes underlying development, stem-cell biology, and disease mechanisms. Professor O’Carroll will explore these regulatory mechanisms in the mouse germ line. His work will concentrate on the importance of the ubiquitous post-transcriptional RNA modifications of transcript uridylation, as well as the direct methylation of cytosine and adenosine bases within cellular RNA. In addition, he will explore the role of RNA-binding proteins in stem-cell function.

Dr Ketan Patel

MRC Laboratory of Molecular Biology, Cambridge

The origin and catabolism of genotoxic aldehydes and their impact on stem cell maintenance

Professors Sir Peter Ratcliffe and Christopher Schofield

University of Oxford

Defining the physiology and therapeutic potential of oxygenases as signalling enzymes

The joint programme aims to link biochemical, physiological and medical perspectives to better define the potential of human 2-oxoglutarate-dependent (2-OG) dioxygenases as therapeutic targets. Both scientists have established track records in relevant fields: Professor Ratcliffe in the discovery and elucidation of physiological pathways that control gene expression in accordance with cellular oxygen levels, and Professor Schofield in the biochemistry and structural analysis of 2-OG oxygenases that catalyse diverse biological oxidations. Their work came together with their joint discovery of a set of 2-OG oxygenases that transduce oxygen-sensitive signals through oxygen-dependent hydroxylation of the transcription factor, hypoxia-inducible factor. From these discoveries, their joint goal is to continue to explore the wider potential of the 2-OG oxygenases as signalling vectors. This will include studying how they react under hypoxic, metabolic and related stresses, and defining the potential for therapeutic targeting in the many human diseases that are characterised by hypoxia and dysregulated metabolism.

Dr Frank Reimann and Professor Fiona Gribble

University of Cambridge

Physiology of the enteroendocrine system

The diffuse enteroendocrine system comprises more endocrine cells than any other endocrine organ in the body, and plays a central role in the coordination of metabolism. Its location within the intestinal epithelium enables it to sample and respond to the availability of nutrients in the external (luminal) environment. The potential for exploiting the enteroendocrine system therapeutically is increasingly recognised. Dr Reimann and Professor Gribble have worked towards characterising signalling pathways in enteroendocrine cells (EEC), but recognise that there are still gaps in the knowledge of how the enteroendocrine axis operates in a physiological setting. They propose to identify diversity in the EEC population influencing the effectiveness of dietary and pharmacological stimuli, and to explore the biology of a newly identified orexigenic gut hormone. Defining the basis for the variability of gut hormone responses in humans and establishing methodology to monitor activity of primary human EEC will open new avenues for studies.

Professor Helen Saibil

Birkbeck, University of London

Molecular and cellular mechanisms of protein aggregation and toxicity in models of neurodegeneration

Protein quality-control systems normally prevent the accumulation of toxic, misfolded species that cause degenerative diseases. Through genetic and biochemical changes of unclear origin, protein quality control becomes less effective with ageing, eventually resulting in late-onset neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. A better understanding of the mechanisms of protein disaggregation would enable new approaches to understanding toxic gain of function, how cells handle aggregates, and the failure of protein quality control in ageing individuals. Professor Saibil plans to investigate the cellular machinery for processing amyloid and related aggregates of misfolded proteins using a combination of molecular and cellular electron microscopy with mechanistic studies.

Professor Mark Woolrich

University of Oxford

Exploring the mechanisms of distributed spontaneous brain activity

July

Professor Jean Beggs

University of Edinburgh

Regulation of splicing and functional links between splicing and transcription

In most eukaryotic genes the information in the DNA sequence is interrupted by noncoding regions called introns. An RNA copy of the gene has to be cut and then spliced back together to remove the introns and produce a continuous message with the correct information to produce a protein. An unexpectedly high proportion of genetic diseases and cancers are caused by splicing defects, and one-third of disease-causing single nucleotide polymorphisms have the potential to disrupt splicing. Professor Beggs will investigate the mechanistic links between pre-mRNA transcription and splicing, including the potential role of splicing-dependent transcriptional checkpoints as a cellular system of RNA quality control.

Dr Ariel Blocker

University of Bristol

Molecular mechanisms powering a bacterial toxin injection device

Type III secretion systems (T3SSs) are essential devices in the virulence of many Gram-negative bacterial pathogens. They translocate protein effectors of virulence into eukaryotic host cells to manipulate the cells during infection. In order to enter the narrow channel at the centre of the T3SS injection needle, substrates must carry a targeting motif and become unfolded. However, the architecture of the cytoplasmic and inner-membrane export apparatus is not well defined. In addition, it is unclear how energy from ATP hydrolysis and the proton motive force is utilised to drive substrate export. Dr Blocker plans to use a combination of genetic and biochemical studies focused around in vitro reconstitution, as well as high-resolution structural approaches, such as electron microscopy and mass spectrometry, in order to investigate these aspects of T3SSs.

Dr Simon Boulton

The Francis Crick Institute

Mechanisms of double-strand break repair pathway choice

DNA double-strand breaks (DSBs) are a major threat to genome stability, as failure to repair them correctly can give rise to chromosome translocations and genome amplification events and is the underlying cause of a number of hereditary cancer predisposition syndromes, such as Fanconi anaemia. The two main pathways for the repair of DSBs are non-homologous end joining and homologous recombination. Dr Boulton will be investigating the role of the protein 53BP1 in the regulation of DSB repair, with the goal of gaining a molecular understanding of how 53BP1 and its cofactors bind and protect DNA ends.

Professor Ian Collinson

University of Bristol

Understanding mitochondrial protein import and membrane insertion

Mitochondria require the import of proteins produced by the host genome in order to carry out their biological function of adenosine triphosphate generation and the exertion and regulation of metabolism. This import is achieved by a collection of complexes located in the mitochondrial membranes, such as the translocon of the outer membrane (TOM) and translocon of the inner membrane (TIM). Professor Collinson aims to undertake a comprehensive analysis of the TOM and TIM complexes in order to determine their 3D structures using cryo-electron microscopy. He is also planning to develop a range of in vitro biochemical and biophysical assays that will enable him to dissect the molecular details of the mitochondrial import process.

Professor Peter Cullen

University of Bristol

Defining the role of retromer in endosomal sorting in health and disease

Retromer, a highly conserved protein complex, is a master regulator of endosomal sorting, with defects in its function increasingly being linked to human disease. The observation of lower levels of retromer expression in the brains of Alzheimer's and Parkinson's disease patients, and the segregation of mutations in retromer and retromer-associated pathway components with Parkinson's disease, have further focused attention on this complex, and, more broadly, on the endocytic network's role in neuroprotection. However, little is known about how retromer works. During his award, Professor Cullen aims to define the inner workings of this machine, reveal fundamental information on cargo-sorting events conserved across eukaryotic phylogeny, and provide an insight into retromer's many roles in development and cell and organism physiology. Applying acquired knowledge to retromer's role in Parkinson's disease will provide unique insight into the cell biology of this disease.

Dr Marcus Dorner

Imperial College London

Determinants of hepatitis B virus interspecies restriction factors

Hepatitis B virus (HBV) affects over 350 million people worldwide and, due to the current inability to cure the infection, requires lifelong treatment. Its narrow host tropism, restricting infection to humans and chimpanzees, has greatly limited our ability to develop new and improved treatment strategies. A better understanding of the HBV life cycle in human and non-human cells could lead to the development of small-animal models to be used in the preclinical evaluation of novel drug candidates. Dr Dorner's research focuses on the identification of non-redundant host factors that are essential for HBV infection in non-human cells, with the aim of creating an immunocompetent small-animal model for HBV.

Professor Charles ffrench-Constant

University of Edinburgh

What are the mechanisms by which myelination in the central nervous system is established and refined?

Dr Alex Gould

The Francis Crick Institute

Mechanisms underlying the developmental origins of adult metabolism and lifespan

There is substantial evidence from human and rodent studies that fetal malnutrition is a major risk factor for developing metabolic diseases, such as type 2 diabetes, during adult life. The identification of the mechanisms by which early-life nutrition can have long-term or programming effects upon adult health is likely to have an impact upon dietary guidelines and other approaches for preventing and treating metabolic disease. Dr Gould will harness the genetic advantages of a newly developed Drosophila model to investigate the nutritional programming of metabolism and lifespan. His aims are to identify new molecular mechanisms responsible for nutritional programming and to define the complex interactions between early-life and adult diets during this process. He will also test the degree to which nutritional programming mechanisms are conserved between Drosophila and mammals.

Professor Philip Goulder

University of Oxford

Mechanisms of HIV disease limitation and cure revealed in paediatric infection

Professor Goulder aims to address the research question of whether a cure can be achieved in an HIV-infected individual. Professor Goulder's lab has identified three groups of children in whom it believes a cure is most likely to arise. These studies are linked by the hypothesis that a cure is possible where there are obstacles to HIV establishing a latent reservoir in long-lived resting T cells. The first group in the study is HIV-infected newborns in whom antiretroviral therapy (ART) is initiated at birth. The second group is HIV-infected children in whom ART was initiated in infancy, now leaving no trace of infection or HIV antibody response. The third group is HIV-infected children over five years old who are entirely healthy and indistinguishable from HIV-uninfected age-matched children, except for high levels of HIV in their blood. This group is key to understanding how disease from HIV can be avoided – and, despite their high levels of HIV, these children may also have cure potential.

Professor Anthony Green

University of Cambridge

CALR mutations and human myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies predominantly affecting older individuals and are associated with an increased risk of thrombosis and acute leukaemia. They provide a powerful approach to studying mechanisms whereby stem and progenitor cells, which are inaccessible in other malignancies, are subverted in the earliest stages of tumorigenesis. Professor Green has identified that somatic calreticulin (CALR) mutations reveal a novel biological pathway that modulates haematopoiesis, and that CALR is a target for tumorigenic mutations. During his award Professor Green intends to explore the function of CALR mutations in order to shed new light on normal haematopoiesis (particularly haematopoietic stem cell behaviour and megakaryopoiesis), MPN pathogenesis and calreticulin function.

Professor Keith Gull

University of Oxford

Cell morphogenesis, development and pathogenicity in trypanosomes

The kinetoplastid parasites that cause trypanosomiasis and leishmaniasis represent major threats to world health and agricultural development. Sustained diagnostic and control efforts have lowered the number of new cases from earlier epidemic proportions. However, this improving picture relies on often-fragile infrastructure for complex diagnosis and treatment. Significant challenges remain for improving trypanocide use for livestock disease, which is still inhibitory to agricultural development. Professor Gull's primary aim is to understand the molecular cell biology of cell form and shape in Trypanosoma brucei and other kinetoplastids in relation to their pathogenicity, life cycle and evolution. This research will provide an integrated view of the trypanosome cytoskeleton, from component proteins to complexes, and the mechanisms of building the high-order organisation of the main structures. It offers a route to understanding dependency relationships in the construction of these structures and how they influence major membrane domains associated with receptor and sensory functions.

Professor Adrian Hill

University of Oxford

A multicomponent high-efficacy malaria vaccine

Exceptionally potent immune responses targeted at key antigens have been required to achieve even partial vaccine efficacy against malaria. A number of advances in recent years have provided the prospect of greatly improved antibody-inducing vaccine components, through the use of both transgenic parasite technology and mass-spectrometry-based sequencing of parasite antigen screening. Professor Hill aims to build on these exciting advances to design and develop an effective multicomponent vaccine against Plasmodium falciparum, the parasite that causes malaria. He aims to do this by: investigating whether a more protective liver-stage vaccine against P. falciparum malaria can be identified by assessing antigens using transgenic parasite technology combined with sequencing of parasite peptides; investigating whether this liver-stage vaccine can be improved by combining it with a new anti-sporozoite vaccine; and investigating whether these components can be efficiently integrated with anti-blood-stage and anti-sexual-stage vaccine components to develop a highly effective multicomponent malaria vaccine.

Professor Paul Kaye

University of York

Host determinants of infectiousness in visceral leishmaniasis

Leishmaniasis is one of the major neglected diseases of poverty, affecting over a million people worldwide, with the most severe form – visceral leishmaniasis, or kala azar – responsible for tens of thousands of deaths every year. This parasitic disease is spread through the bite of a female sandfly that has become infected by biting someone who is either sick from the disease or carrying the parasite without knowing it. To develop tools that will help break the cycle of disease transmission, more needs to be known about how these parasites spread around the body, how they are acquired by sandflies and how variations in host immune responses affect these processes. Professor Kaye's research addresses these questions using new animal models of leishmaniasis transmission, state-of-the-art techniques in cellular immunology and molecular pathology, and computational modelling. The research will provide new knowledge directly applicable to the fight to eliminate this devastating disease.

Dr Jean Langhorne

The Francis Crick Institute

The pir gene family: chronic infection, immunity and virulence

Multigene families are present on most of the chromosomes of the malaria parasite Plasmodium. One gene family, pir (Plasmodium interspersed repeat), is present in all Plasmodium genomes sequenced so far. Despite their discovery more than ten years ago, the function of pir genes is not understood. Recent results from Dr Langhorne's laboratory suggest that they may be virulence factors. Dr Langhorne plans to use a well-defined animal model to discover the interactions of pirs with the mammalian host, which could explain their role in virulence or in other host-parasite interactions. An investigation of the biology of this gene family and its interactions with the host may be key to understanding malaria pathogenesis, and could change our ideas about the relationship between the immune response and virulence. The knowledge gained will promote new research directions and aid new approaches to intervention.

Professor Eric Miska

University of Cambridge

Transgenerational epigenetic inheritance: adaptation, genome stability and evolution

Professor Chris Newbold

University of Oxford

Multigene families in malaria

It has been known for some time that proteins encoded by the var multigene family in human malaria that are expressed on the surface of the infected red cell are extremely important in both pathogenesis and the development of host immunity. More recently, evidence from a rodent malaria model has implicated a second, larger multigene family known as pir (Plasmodium interspersed repeat), common to all species of malaria and an important determinant of virulence. Both families are extremely polymorphic. Professor Newbold's group have developed algorithms that allow accurate assembly of these gene families from next-generation sequencing of large numbers of field isolates. These studies have revealed an unexpected level of sequence sharing both within and between continents. Using analysis of these data, Professor Newbold's group will investigate how this sequence sharing relates to the development of cross-reactive antibodies and immunity, and whether the pir family is also important in the virulence of human malaria.

Professor Anna Christina Nobre

University of Oxford

'Premembering' perception in the human brain

Professor Nobre studies the neural systems that support cognitive functions in the human brain. She is particularly interested in the influence of memory on perception. Memories are essential for bringing together fragments of past experiences, but they are equally important for guiding predictions that help create new sensory experiences. Professor Nobre has dubbed this process 'premembering'. During her award she plans to examine how memory-based expectations combine with current task goals to shape neural activity in anticipation of perceptual events unfolding in dynamic environments. She plans to elucidate the psychological and neural mechanisms of premembering using a range of experimental techniques, including psychophysics, magnetoencephalography, functional magnetic resonance imaging and transcranial magnetic stimulation.

Dr Luca Pellegrini

University of Cambridge

Macromolecular mechanisms of genome duplication and stability

Each time a cell divides, it needs to duplicate its DNA in order to transmit a complete set of genetic instructions to each daughter cell. Inside the cell, dedicated collections of protein molecules cooperate in space and time to execute the biochemical process of DNA replication, upon which genetic inheritance depends. Research in Dr Pellegrini's laboratory aims to understand, at the atomic level, how the proteins and enzymes of DNA replication carry out their vital task. Ultimately, the lab's work will provide a detailed description of the molecular mechanisms by which the cell achieves the remarkable feat of genomic duplication. In addition to its biological importance, this knowledge is of great medical relevance as faults in DNA replication are a major predisposing cause of disease. Dr Pellegrini plans to exploit the knowledge of the three-dimensional structures of replication proteins to identify potential inhibitors that could be developed as novel treatments for cancer.

Professor Jordan Raff

University of Oxford

A molecular analysis of centriole, centrosome and cilium assembly and function

Centrioles organise the assembly of two important eukaryotic cell organelles: the centrosome and the cilium. Centrosomes are the major microtubule-organising centres in many animal cells, and play an important role in cell division, in establishing and maintaining cell polarity, and in positioning and transporting molecules and organelles within the cell. Most cells in the human body form a single, immotile, primary cilium, which can play a vital role in cell signalling and in mechano- and chemo-sensation. There is increasing evidence linking the dysfunction of centrosomes and cilia to a plethora of human diseases, including cancer, kidney disorders, obesity and macular degeneration. Using Drosophila as a model organism, Professor Raff aims to understand how centrioles, centrosomes and cilia assemble and function at the molecular level, the main challenge being to understand how these proteins interact and how their assembly is regulated.

Dr Felix Randow

MRC Laboratory of Molecular Biology

How pathogenic cytosol-dwelling bacteria escape from autophagy

Dr Randow is interested in how individual cells defend themselves against infection. Bacteria that colonise the host cytosol encounter specific anti-microbial defences, and therefore have developed specific adaptations to antagonise these cell defences. Over the last few years autophagy has emerged as a major defence system for the host cytosol. To improve our understanding of anti-bacterial autophagy and to develop novel strategies against professional cytosol-dwelling bacterial pathogens, Dr Randow will investigate how cytosol-dwelling bacteria escape from autophagy, whether we can artificially enforce anti-bacterial autophagy against professional cytosol-dwellers, and which additional cell-autonomous defences are deployed in activated cells to detect and destroy professional cytosol-dwelling bacteria. This research will be crucial for future attempts to manipulate pathogen recognition and vaccine-mediated immunity.

Professor Trevor Robbins

University of Cambridge

Frontostriatal systems in impulsive-compulsive disorders

Professor Robbins studies the relationship between dysfunction in discrete neural systems and the impulsive and compulsive behaviour that accompanies some psychiatric disorders such as obsessive-compulsive disorder, attention-deficit hyperactivity disorder and stimulant drug addiction. An overarching goal of his work is to increase our understanding of the neural mechanisms governing cognitive control. As part of his award, Professor Robbins plans to test whether abnormal compulsions are a result of aberrant stimulus-response habit learning that is potentially exacerbated by impaired anxiety and cognitive control. To do this, he will use state-of-the-art experimental techniques such as DREADDs (designer receptors exclusively activated by designer drugs), optogenetics and neuroimaging to study and compare animal models of impulsivity and compulsivity with key patient populations.

Professor Dame Carol Robinson

University of Oxford

The effects of drug and lipid binding on the structure and function of membrane proteins in health and disease

Membrane-spanning proteins lie at the heart of many human diseases and constitute important drug targets, but little is currently known about the importance of their interactions with the lipid bilayer to their normal function. Professor Robinson plans to use mass spectrometry to investigate whether specific lipid-binding sites exist on membrane proteins and whether they have a major effect on the behaviour and stability of membrane proteins. Professor Robinson also aims to study the potential role of post-translational modifications of membrane proteins in regulating their function and interactions with the lipid bilayer.

Dr Luiz Pedro Sorio de Carvalho

The Francis Crick Institute

Uncovering nutrient acquisition and metabolism in Mycobacterium tuberculosis

Human tuberculosis still claims over a million lives annually, and the spread of multidrug-resistant strains increases the global health impact of the disease. Despite over 100 years of research since its identification we still do not know much about what Mycobacterium tuberculosis 'eats' during infection. In addition, we do not know how host-imposed stresses affect nutrient acquisition. Using virulent M. tuberculosis and a multidisciplinary approach centred on the use of metabolomics, Dr Carvalho aims to identify nutrients that are important during infection, define their transporter systems, map downstream metabolic pathways and pinpoint the nutrients' functions in cellular physiology during infection. This knowledge will significantly increase our understanding of the core processes required for M. tuberculosis survival and pathogenesis. A number of these identified pathways and proteins might represent ideal targets for the development of novel antitubercular agents, which are urgently needed to treat increasingly prevalent antibiotic-resistant infections.

Dr Tony Southall

Imperial College London

Reprogramming neurons for nervous system repair

The brain is one of the most complex biological systems and consists of billions of neurons that possess very diverse morphologies, neurotransmitter identities, electrical properties and preferences for synaptic partners. Understanding how neuronal fates are specified is important to our understanding of neuronal development and neural dysfunction. Dr Southall aims to identify the transcription factors that attribute neurons with particular neurotransmitter identities, and to study whether these transcription factors are able to reprogramme neurotransmitter identity in vivo. Using Drosophila as a model organism, Dr Southall will use a novel technique that allows specific neuronal populations to be profiled with ease, with the aim of identifying the major transcription factors involved in specifying different neuronal properties and reprogramming properties in vivo.

Professor Stephen Wilson

University College London

How is brain asymmetry established and what is it good for?

Nervous system asymmetries influence cognition and behaviour and usually arise during development under the influence of both genetics and environment. Asymmetries may confer advantages through increasing neural capacity and by reducing conflict between hemispheres, and it is likely that the nervous systems of all bilaterally symmetric animals are left-right asymmetric with respect to the processing of information and control of behaviour. In addition to asymmetry being a feature of normally functioning nervous systems, laterality defects are observed in some neurological conditions. Although an important feature of the nervous system, the developmental and genetic bases of brain asymmetries remain obscure. Professor Wilson will use developmental, genetic, imaging and behavioural approaches in zebrafish to address how asymmetries arise in development, how they are encoded in circuits and what their importance is for nervous system function, in order to gain a better understanding of the brain in health and disease states.

April

Professors John Aggleton and Shane O'Mara

Cardiff University and Trinity College Dublin

The cognitive thalamus: more than a relay

Research on the biological basis of episodic memory has traditionally focused on the functioning of the hippocampus, a brain structure in the medial temporal lobe. Professors Aggleton and O'Mara are interested in studying how other brain areas play important roles in the formation, maintenance and recall of episodic memories. They are particularly interested in the thalamus, a structure in the middle of the brain. Their recent research has shown that neurons in the thalamus signal multiple types of spatial information, providing new insight into why this area might be so critical for memory. Professors Aggleton and O'Mara plan to elucidate the path that spatial information travels to reach the thalamus and to determine the impact of thalamic neurons on spatial memories. This work could help explain how networks of brain areas beyond the medial temporal lobes work with the hippocampus to shape memory.

Dr Becca Asquith

Imperial College London

Inhibitory killer immunoglobulin receptors and virus-specific adaptive immunity in humans

Killer immunoglobulin receptors (KIRs) are known to be associated with innate immunity, but the role of KIRs in adaptive immunity is virtually unknown. Dr Asquith has evidence that KIRs can modulate the adaptive response, with direct consequences for human health. She will now investigate the mechanisms underlying this modulation in viral infection using a combination of theory and experimental methods. She has three main aims: to investigate whether KIR2DL2 enhances T-cell survival in vivo during HTLV-1 and HCV infections; to determine new models to distinguish causality from correlation between KIRDL2 and lymphocyte survival; and to identify genes involved in KIRDL2-mediated enhancement. Dr Asquith will also assess whether inhibitory KIRs enhance adaptive immunity in two globally important virus infections. Specifically, she will examine whether KIRDL2 could be a predictor of the outcome of HIV-1 infection, and the impact of KIR genotype on the longevity of CD8 T-cell responses to yellow fever vaccine.

Professor Andrew Biankin

University of Glasgow

Defining platinum- and PARP-inhibitor-responsive molecular phenotypes of pancreatic cancer

The overall aim of Dr Biankin's research is to advance innovative approaches in cancer genomics for therapeutic development, with the aim of defining, understanding, testing and implementing personalised therapeutic strategies for pancreatic cancer. This research will focus on identifying patients who will respond to platinum-based therapies (which are emerging as the standard of care) and to PARP inhibitors that target similar mechanisms, so that only those who are likely to benefit receive these drugs. This also allows those who are unlikely to respond to avoid the toxicity of ineffective therapies and to receive treatments that are more likely to benefit them as individuals.

Professor Andrea Brand

University of Cambridge

Nutritional control of neural stem-cell quiescence and reactivation

The systemic regulation of stem cells ensures that they meet the needs of the organism during its growth and in response to injury. Stem cell populations in varied tissues spend much of their time in a mitotically dormant (quiescent) state; a key element of regulation is the decision between quiescence and proliferation. Using Drosophila as a model organism, Professor Brand aims to uncover how the environment, both systemic and local, influences neural stem-cell behaviour and the molecular mechanisms that control neural stem-cell quiescence and reactivation, in order to gain insights into tissue regeneration under normal and pathological conditions and in response to ageing.

Professor Neil Bulleid

University of Glasgow

Protein folding and thiol modification in the mammalian endoplasmic reticulum

The correct folding and assembly of proteins is the final stage in cellular protein synthesis. Protein folding requires a group of proteins that can either catalyse folding reactions or function as molecular chaperones to prevent non-productive protein aggregation. The lack of correct folding can lead to stress responses that ultimately cause diseases such as diabetes and cancer. Professor Bulleid will be investigating the molecular mechanisms that cells use to ensure that the chemical environment inside the endoplasmic reticulum enables the correct folding and assembly of secretory proteins. He will also study the regulation of protein folding by the modification of thiol chemical groups.

Dr Marco Catani

King's College London

Lateralisation of human brain networks: implications for stroke recovery

A distinctive feature of the human brain is that certain cognitive functions, such as our ability to use language, tend to be lateralised to one side of the brain or the other. This phenomenon has been extensively studied, but little is known about whether the networks of neurons that connect distinct areas in the brain are similarly lateralised. Dr Catani will use advanced neuroimaging techniques to map patterns of neural network lateralisation in the brain and relate these patterns to cognitive function. Specifically, he will examine lateralisation of neural networks related to language function and visuo-spatial attention in both healthy participants and patients who have stroke-related brain damage. This work could significantly increase our understanding of the complex relationship between brain structure, behaviour, and recovery following stroke. 

Professor Paul Crocker

University of Dundee

Molecular dissection of siglec-mediated regulation of neutrophil inflammatory responses

Neutrophils play crucial roles in host defence against bacterial and fungal pathogens. The regulation of neutrophil-endothelial cell interactions is important to prevent damage, especially in the lungs, where there is a vast network of narrow capillaries. Professor Crocker has focused for the majority of his career on the discovery and characterisation of the siglec family of sialic acid-binding Ig-like lectins. He has recently identified a new siglec inhibitory pathway that controls β2-integrin-dependent neutrophil recruitment following exposure to lipopolysaccharide His goal is to understand the molecular mechanisms of how neutrophil-expressed siglecs in mice (siglec-E) and humans (siglec-9 and siglecs-5 and -14) regulate neutrophil functions during inflammation. Professor Crocker will undertake detailed proteomic and glycomic analysis of siglec signalling complexes and siglec counter-receptors and ligands on endothelial cells in order to provide new opportunities for the treatment of diseases such as acute lung injury.

Professor Robert Cross

University of Warwick

How kinesins generate directional force and movement

Kinesin molecular motors are walking machines that transport cargo along microtubules in cells. Kinesin-driven transport is a core organising principle of eukaryotic life, driving a variety of self-organisation processes, for example mitosis, meiosis and axonal transport. Professor Cross's research asks how kinesin motors work at the molecular level. To answer this fundamental question, he will use a variety of protein engineering, microscopic and computational approaches, including single-molecule optical trapping microscopy.

Professor Alun Davies

Cardiff University 

Tumour necrosis factor superfamily forward and reverse signalling in neural development

Professor Davies studies the molecular mechanisms that govern the survival of neurons and the growth of neuronal processes (axons and dendrites) during development. His team has recently discovered that members of the tumour necrosis factor (TNF) family of extracellular signalling proteins play important roles in regulating axon growth. Professor Davies plans to study how different TNF proteins orchestrate the establishment of patterns of neural connectivity during development, and to unravel the molecular mechanisms underlying this. The results of Professor Davies's work will further our understanding of how the nervous system is wired up, and may shed light on what goes awry in certain neurodevelopmental disorders.    

Professor Julian Downward

Institute of Cancer Research

Investigation of circulating tumour DNA in the early detection of KRAS and EGFR mutant cancers

In common solid tumours where RAS or EGFR mutations are frequent, early surgical intervention is the most effective therapeutic approach. The most important limitation to the use of curative surgery is that patients present with cancers that have already spread beyond their primary site. Improved ability to detect cancers at a very early stage would allow greater usage of surgical intervention. While advances in the early detection of cancer are occurring on many fronts, developments in recent years have come from the ability to analyse tumour-derived DNA in circulating blood, either as circulating free-tumour DNA fragments or in circulating tumour cells. Professor Downward aims to investigate the potential of circulating free-tumour DNA to enable the early detection and characterisation of cancers, and to determine whether circulating free-tumour DNA is likely to have a utility as a tool for detection of cancers in the clinic.

Dr Sherif El-Khamisy

University of Sheffield

The repair of oxidative and topoisomerase-induced chromosomal breaks: mechanisms and implications for human health

Breakage of a single strand of DNA is the most abundant DNA lesion in cells. It arises from oxidative damage or the actions of DNA ligases or topoisomerases. If these DNA breaks are not rapidly repaired then transcription can be impaired and double-strand DNA breaks can become more likely to occur during cellular replication. Dr El-Khamisy's research focuses on understanding the molecular mechanisms for the repair of oxidative and protein-linked DNA breaks in health and disease.  

Dr Thomas Ezard

University of Southampton

How does natural and anthropogenic disturbance change short- and long-term human population growth?

Dr Ezard is an evolutionary ecologist interested in the dynamic consequences of how the structure of populations and communities interacts with environmental change. He is examining this through developing the interfaces between mathematical and statistical models. He will address his research question by constructing a database of momentum in human populations and using it to dissect the demographic, environmental and social drivers of human transient dynamics, from city to global scales. This research will provide insights into the drivers of short- and long-term population growth, elucidating how world wars, global pandemics, revolutions, catastrophic floods, political acts and social change shape societal responses to contemporary events. Dr Ezard's work will contribute to the much-needed evidence base on the dangers and benefits that momentum poses for population health in the 21st century.

Professor Kate Jeffery

University College London

Neural encoding of complex space

Humans and animals are remarkably good at moving through a complex and ever-changing world. Professor Jeffery explores how the brain integrates different forms of sensory information to make spatial navigation possible. Professor Jeffery aims to investigate how neurons in the brain represent large areas of previously explored space. Prior work has shown that several classes of neurons communicate and store information about our immediate surroundings. Professor Jeffery will test the hypothesis that these local representations of space are connected in the brain to form a master map of our world, utilised for navigation beyond local environments. The work could significantly increase our understanding of the neural basis of spatial navigation, while also providing insight into disorders of orientation and spatial memory.

Professors Nicholas Luscombe and Jernej Ule

University College London

The role of 3' untranslated region variation in the molecular pathogenesis of motor neurone disease

3' untranslated regions (3' UTRs) play critical roles in the control of mRNA translation and stability by presenting sequence motifs and secondary structural elements that mediate interactions between the mRNA and other factors such as proteins or miRNAs. Recent studies have demonstrated that human genetic variations in UTRs and variations in promoter sequences impact upon gene expression to a similar degree. Professors Luscombe and Ule hypothesise that 3' UTR sequence variation disrupts mRNA stability and translation, which can contribute to the pathogenesis of diseases such as cancer or neurodegeneration. They will use genetic and biochemical investigations in differentiated human motor neurones combined with computational modelling to study the impact of alternative 3' UTRs on health and disease.

Professor Keith Matthews

University of Edinburgh

Environmental sensing and cell-cell communication in African trypanosomes

Professor Matthews proposes a global approach to understanding the molecular mechanisms that control infection by the African trypanosome, the parasite responsible for sleeping sickness in humans and related diseases in cattle. Sensing of the environment by trypanosomes is central to both autoregulation of growth in the bloodstream and the cellular differentiation necessary for transmission by the tsetse fly vector. Professor Matthews's aims are: to develop a further understanding of the control of population density and growth regulation in infected mammals; to investigate interspecies competition; and to determine the molecular mechanisms underlying the perception, transmission and execution of signals for the differentiation that follows the transfer to a tsetse fly. This work could lead to a better understanding of the processes by which the pathogenic bloodstream forms limit infection while maximising transmissibility to the insect vector, and how the parasites respond to environmental signals upon ingestion by the tsetse fly.

Professor Oscar Marín

King's College London 

General principles underlying the assembly of cortical inhibitory circuits

Dr Marín is a neuroscientist studying the growth, movement and wiring of interneurons in the cerebral cortex, the outermost layer of the brain. He will explore how the development of inhibitory interneurons influences the structure and function of the cerebral cortex. Specifically, he hopes to elucidate the genetic and molecular factors in the brain that influence interneuron lineage, location and wiring. He also plans to investigate the mechanisms that emerge within populations of neurons to drive the identity, distribution and number of cortical interneurons. Dr Marín's work could shed light on the pathophysiology of disorders such as epilepsy, autism and schizophrenia, while also bringing us a step closer to understanding how brain function might arise from the assembly of neural circuits. 

Professor David Newby

University of Edinburgh

Identification and prediction of coronary artery plaque rupture using 18F-fluoride positron emission tomography

There are approximately 150,000 myocardial infarctions per annum in the UK, but patients are not stratified to identify those who would most likely benefit from currently available treatments. Professor Newby believes that a better understanding of the biology of atherosclerotic plaque and the classification of necrotic and inflamed coronary atherosclerotic plaques will help clinicians identify those at a high risk of recurrent cardiac events. Professor Newby will use a non-invasive imaging technique to investigate whether the identification and quantification of plaque inflammation and rupture could enable a more focused, effective and efficient method of tailoring therapy. This approach could prevent unnecessary and potentially harmful invasive investigations (invasive coronary angiography) and treatments (percutaneous coronary intervention and coronary artery bypass graft surgery), as well as lead to better targeting of secondary preventative drug therapies, avoiding harmful side effects.

Dr Snezhana Oliferenko

King's College London

A comparative approach to understanding nuclear division

Mitotic division ensures the faithful inheritance of genetic material in proliferating eukaryotic cells. Errors in this process often lead to developmental defects and disease. The cellular genome is enclosed within the nucleus, which is bounded by a double membrane termed the 'nuclear envelope'. To facilitate the inheritance of genetic material, eukaryotic cells use a diverse set of cell type-specific and organism-specific mechanisms, which range from fully 'open' to fully 'closed' mitosis with varying degrees of nuclear envelope breakdown. Dr Oliferenko will investigate the mechanisms that cells use to dynamically restructure the nuclear envelope during mitosis to allow chromosome segregation and the formation of daughter nuclei.

Professor Antonella Riccio

University College London

Epigenetic regulation of neuronal development

Professor Riccio is a neuroscientist studying chromatin – the mix of DNA and proteins that makes up the nuclei of cells. She is particularly interested in how physiological stimuli, such as neurotrophins, neurotransmitters and synaptic activity, induce dynamic changes in chromatin and associated gene expression. Professor Riccio plans to explore the molecular mechanisms that allow the neurotransmitter nitric oxide to modify chromatin in developing neurons. Her research will help elucidate how external stimuli drive heritable changes in neurons. This work could also further our understanding of neurodegenerative disorders caused by mutations in the proteins that regulate chromatin.

Dr William Schafer

University of Cambridge 

Identifying novel sensory molecules and mechanisms in nematodes and mammals

Our senses of taste, touch and hearing depend on ion channels embedded in sensory receptors. External sensory stimuli trigger these channels, causing their associated sensory receptors to fire. The molecular mechanisms that govern these types of sensory receptors and their ion channels are still poorly understood. Dr Schafer plans to examine a family of genes – the transmembrane channel-like (TMC) family – that may encode channels important for our senses of hearing, taste and touch. To do this, he will study the properties, functions and genetics of TMC proteins in mammalian cells and genetically modified Caenorhabditis elegans, or roundworms. The work will increase our understanding of how the nervous system transforms sensory stimuli into neural signals. It could also provide new insight into the nature and treatment of sensory disorders, such as deafness and chronic pain.

Professor Andrew Sharrocks

University of Manchester

Shaping transient transcriptional responses

Cell signalling often results in transient transcriptional responses in which genes are initially activated before being turned off again and reset in readiness to respond to the next wave of signal. This type of transcriptional response is associated with many biological processes where timing is essential, such as cell cycle regulation, differentiation, development, neuronal cell activation and immune responses. We know a lot about the activation phases but very little about the 'off' phases. Professor Sharrocks will redress this balance by studying the mechanisms by which transcription is terminated and held in a refractory state, and how the transcriptional machinery is then reset from this refractory state so that it is ready to be reactivated.

Professor Peter Simmonds

University of Edinburgh

The role of genome composition and the structure of mammalian RNA viruses on their host interactions, pathogenesis and transmission

RNA viruses, which form the majority of emerging pathogens affecting humans and animals, are remarkably adapted to evade and inhibit powerful host cellular and systemic immune responses to infection. In addition to encoding specific immune-evasion proteins, RNA virus genomes display several compositional features, such as skewed dinucleotide frequencies, that profoundly modify interactions with cellular defence mechanisms. Professor Simmonds is launching a new area of research to understand recognition mechanisms and the role of these global configurations in the pathogenesis, evolutionary fitness and transmission of RNA viruses. His approach is to investigate why and how certain sequence motifs in the genome are selected over evolutionary time and what fitness trade-offs are involved from a virus point of view. Newly discovered methods to accelerate or attenuate RNA virus replication can be exploited in vaccine or transgene technology.

Dr Katharina Simon

University of Oxford

The role of autophagy in quiescence of healthy hematopoietic cells

Autophagy is the major pathway for degradation of macromolecules in cells. However, the contribution of autophagy to the maintenance of healthy long-lived cells has not been investigated in normal physiological settings. Dr Simon has obtained preliminary data showing that the quiescent status of long-lived cells, such as hematopoietic stem cells (HSCs) and memory T cells, is autophagy-dependent. Dr Simon has two key aims to address in her work: to determine whether autophagy is required for HSC quiescence and to assess the molecular mechanism regulating this process; and to understand the role of autophagy in memory CD8 T-cell formation. The molecular mediators and mechanisms identified by Dr Simon's work have the potential to highlight new targets for improving regenerative medicine approaches, and could shed light on mechanisms of immune ageing and new avenues for cancer therapy, as well as contributing to improved vaccine development.

Dr Shankar Srinivas

University of Oxford

Control of epithelial cell migration

Many functions associated with epithelia during development, growth, disease and repair require them to be highly dynamic while maintaining robust structural integrity. Although extensive remodelling of epithelial sheets underpins key morphogenetic events during embryonic development, relatively little is known about how this remodelling is coordinated across the various scales of molecules, cells and tissues, or how it is modulated to achieve diverse epithelial forms. A major focus of Dr Srinivas's research is on understanding the cellular and molecular basis for the directional and coordinated migration of a group of embryonic epithelial cells called the anterior visceral endoderm, whose movement is essential for the correct orientation of the head-tail axis. Insight from this research, in addition to illuminating fundamental processes in embryogenesis, will also inform our understanding of core aspects of cell biology, such as the regulation of cell movement, a process often subverted in pathological situations.

Professors Paul Williams and Morgan Alexander

University of Nottingham

Bacterial surface sensing – to stick or not to stick?

Reducing the risk of infection associated with in-dwelling medical devices has huge public health significance. Professors Williams and Alexander propose to build on their discovery of bacteria resistant polymers (BRPs) and their use in in-dwelling medical devices. The mechanism by which these BRPs resist attachment is, however, not understood. The key mysteries are how bacteria respond dynamically to polymer surfaces, and what intra- and intercellular signalling mechanisms bacteria employ to sense and respond to these surfaces. Professors Williams and Alexander propose an interdisciplinary approach, combining materials science and molecular microbiology, in conjunction with high-resolution state-of-the-art imaging, exploiting the extensive material chemistry and attachment phenotypes. A closer understanding of the mechanisms used by bacteria to interact with polymer surfaces could inform the rational design of improved BRPs in the future and achieve a transformative change in preventing device-centred infections.

Dr Douglas Winton

University of Cambridge

Fundamental and applied biology of intestinal stem cells

The critical dynamics that underpin most of the cell and tissue biology of any renewing tissue are the relative capacities of cells to generate and support clonal progeny. However, the repertoire of behaviours by which stem cells achieve, maintain and alter their self-renewing function is still not well understood. A major focus of Dr Winton's research is to understand the relationship between the small number of equipotent stem cells and the extensive heterogeneity in the expression of stem-cell markers that associate with stem-cell function. In addition, Dr Winton aims to understand the dynamics of human stem-cell renewal that determine the number and replacement rate of stem cells in the human intestine, and how these dynamics change in intestinal pathologies.

2013

December

Professor Gordon Brown

University of Aberdeen

C-type lectins in antifungal immunity

Professor Brown's work has established that C-type lectin receptors are critical for protective antifungal immunity. However, there is still much to discover in terms of the roles of these receptors and their therapeutic potential. During his award, Professor Brown will build on his exciting recent observations to investigate in detail how C-type lectins facilitate immune recognition and responses to fungi and how these responses can be both beneficial and detrimental to the host.

Professor Jonathan Clarke

King's College London

Cellular and molecular regulation of early brain development

The remodelling of cell shape and cell-cell junctions is of fundamental importance during the morphogenesis of many body organs. As well as being critical to building an embryo, misregulation of these processes may underlie serious disease states such as cancer, where cell behaviour is remodelled with potentially disastrous consequences. Professor Clarke aims to understand the cell biology of individual cells in the relatively complex environment of a living embryo's brain. Specifically, he will address how progenitor-cell shape and connectivity are remodelled during the morphogenesis and neurogenesis of the brain. The development of neuron morphology is of fundamental importance as it is one of the major factors that can contribute to neuronal connectivity and hence brain function.

Professors Anne Dell and Brendan Wren

Imperial College London and London School of Hygiene and Tropical Medicine

Deciphering the bacterial glycocode

Glycoproteins are ubiquitous biomolecules involved in many biological processes ranging from immunity recognition to cancer development. In eukaryotes, glycosylation is known to impart novel biological and physical roles by providing labels for cell-cell communication and assisting in protein stabilisation. However, the role of glycosylation in bacteria and pathogenesis remains poorly understood. Recent evidence for protein glycosylation being central to the survival and pathogenesis of many bacteria suggests it is an ideal target for disabling them. Professors Dell and Wren will investigate the molecular, structural and functional basis of glycosylation in pathogenic bacteria, which will provide new avenues for antibiotic and vaccine design.

Professor Antony Galione

University of Oxford

Two-pore channels and NAADP-mediated endolysosomal Ca2+ signalling in health and disease

Calcium ions are important signalling molecules regulating a multitude of processes, from fertilisation to cell death. Different stimuli and their combinations generate specific spatiotemporal calcium signals, which are decoded into distinct cellular responses. Cracking this code requires a detailed understanding of the spatial and temporal choreography of the messengers, proteins and organelles that generate these calcium signatures. Nicotinic acid adenine dinucleotide phosphate (NAADP) is unique in evoking calcium release from acidic endolysosomes, and recent work suggests that two-pore channels (TPCs) – a novel family of endolysosomal channels – are the target calcium channels for NAADP. Professor Galione's research aims to clarify fundamental aspects of NAADP signalling, particularly mechanisms by which cellular stimuli induce changes in NAADP levels, how NAADP mobilises calcium from the endolysosomal stores (particularly the precise roles of the TPCs), and the specific roles of endolysosomal calcium stores in (patho)physiological processes.

Dr Mark Isalan

Imperial College London

Gene network engineering: quantifying emergent gene expression in cancer and antibiotic resistance

Dr Isalan aims to understand and build gene networks that behave predictably, consistently and robustly in the context of solving medically relevant problems. Specifically, his research will explore the emergence of gene expression in response to need in the context of antibiotic-resistance genes in bacteria and multidrug-resistance genes in cancer cells. The main concept at the centre of his research is that natural selection occurs not only at the level of the gene (on genetic variation), but also at the level of gene expression, influencing heritable phenotypic variation. By combining laboratory experiments and computational modelling, he aims to develop a new theoretical basis for understanding emergent gene expression.

Dr George Kassiotis

The Francis Crick Institute

Mechanisms of endogenous retrovirus activation by microbial exposure

Co-infections can compromise key aspects of the immune control of endogenous retroviruses (ERVs). Dr Kassiotis will take a broad but coherent approach to the question of how ERVs are regulated by the immune system and microbial infection. His overall aim is to understand the regulation of ERV expression and its interplay with gut microflora, using a combination of approaches that include mouse models and surveys of human samples. Results could lead to important discoveries that will transform our understanding of ERVs and human disease.

Dr Claudia Kemper

King's College London

Complement receptor signalling in Th-1 immunity

Complement is critically important in human health and disease. Dr Kemper's research seeks to define the function of complement in the regulation of adaptive Th1-mediated inflammation and autoimmune diseases, such as rheumatoid arthritis and scleroderma. She will investigate how the autocrine-activated receptor-signalling network regulates Th1 immunity, how dysregulation of these pathways contributes to Th1-driven autoimmune diseases, and how druggable targets in these pathways can be exploited to have a therapeutic impact upon autoimmunity.

Professor Karim Labib

University of Dundee

Functional dissection of the eukaryotic replisome

One of the most important challenges for proliferating cells is to make a single and precise copy of each chromosome before cell division. This is achieved by a complex molecular machine called the replisome. Professor Labib aims to identify and understand the unique features of the eukaryotic replisome that are critical for the duplication and stable inheritance of eukaryotic chromosomes, but which are not shared with the much better characterised replisome of E. coli. A stronger understanding of chromosome replication is important: defects in chromosome replication are an early feature in the pathogenesis of cancer, and so may provide a target for the future development of new therapies to selectively target cancer cells.

Professor Leon Lagnado

University of Sussex

Synaptic computation in the visual system

Professor Lagnado will be using his Investigator Award to study how the retina and visual cortex carry out computations that are important for our sense of vision, such as detecting changes in contrast or estimating the orientation of an object. He will ask how these computations are modified in response to changes in visual input that lead to adaptive changes in processing, and in response to neuromodulators that alter circuit function on longer timescales. He is particularly interested in defining the roles of excitatory and inhibitory synaptic connections during these processing tasks. A feature of his approach is the imaging of activity across large populations of synapses and neurons. His guiding hypothesis is that the plasticity of neurotransmission plays a major part in altering the input-output relation of sensory circuits. The insight provided by this research will help us understand fundamental mechanisms by which neural circuits process information from a changing world.

Dr Kevin Maloy

University of Oxford

Regulation of intestinal immune homeostasis by NOD-like receptors

Professor Walter Marcotti

University of Sheffield

The development and function of the mammalian auditory circuitry

Professor Marcotti is studying how the auditory system develops and operates normally, and how defects at the molecular level can lead to deafness. He is doing this by investigating the physiological properties of the individual sensory hair cells of the mammalian cochlea, using electrophysiological, calcium-imaging and molecular-biology techniques. He will apply these techniques to unravel the physiological and genetic mechanisms that lead to the assembly of the proteins required for sound encoding, and, in so doing, aims to discover how inner hair cell synapses control the transfer of sound information to auditory fibres in vitro and in vivo.

Professor Juan Martin-Serrano

King's College London

Exploring the final events in eukaryotic cell division

Professor Martin-Serrano's research is focused on understanding how the last events in eukaryotic cell division are coordinated so as to prevent damage to any lagging chromosomes. The physical separation of daughter cells, termed abscission, is a fundamental process in biology that occurs as the final cytokinetic event, as it results in the physical cleavage of the midbody that forms between daughter cells. Professor Martin-Serrano is studying the mechanism that promotes midbody abscission, and how this process is regulated by a checkpoint process called NoCut, which can delay abscission where necessary to prevent genetic damage. His overall aim is to identify the molecular mechanisms underlying this process.

Dr Elizabeth Murchison

University of Cambridge

Genome diversity and evolution in transmissible cancers in dogs and Tasmanian devils

Tasmanian devil facial tumour disease (DFTD) and canine transmissible venereal tumour (CTVT) are the only known examples of naturally occurring clonally transmissible cancers. They are clonal cell lineages that have survived beyond the deaths of the individual hosts that spawned them by acquiring adaptations for the transfer of living cancer cells between hosts. Dr Murchison will catalogue genetic and phenotypic diversity in hundreds of DFTD and CTVT tumours found in geographically dispersed locations. She will use genetic data to explore how these two infectious diseases first arose and subsequently spread through their host populations, and she will investigate how tumour phenotypic diversity may be influenced by genetic and environmental change. She will analyse patterns of selection operating on the two lineages in order to understand factors that have influenced transmissible cancer evolution. In addition, she will investigate the frequency of horizontal DNA transfer in clonally transmissible cancers.

Dr Simon Newstead

University of Oxford

Mammalian peptide transporters as targets for advanced drug design and delivery

Dr Newstead will be investigating at the molecular level the structure and function of the mammalian proton-coupled peptide transporters PepT1 and PepT2, which are important for the uptake of dietary protein and provide a major route for the absorption of drugs. Currently, there is no clear molecular understanding of how PepT1 or PepT2 recognise and transport peptides or drug molecules. The binding sites of PepT1 and PepT2 have to accommodate peptides that vary significantly in size, charge and hydrophobicity, which means that they can also transport chemically diverse drug molecules. The results of Dr Newstead's work should enable the rational design of drugs with improved oral bioavailabilty, through insights gained from the use of sophisticated structural, biochemical and functional studies.

Professor D James Nokes

University of Warwick

Defining pathways of respiratory virus transmission leading to improved intervention strategies

The transmission dynamics of human respiratory viruses are fundamentally linked to the organisational structure of person-to-person contact throughout a population, whether at the household, school, local community or national level. Professor Nokes aims to uncover potential pathways of transmission determined by contact structures, so as to gain greater insight into the emergence, spread, persistence and control of major viral causes of respiratory disease, including influenza, respiratory syncytial virus, coronaviruses and rhinoviruses. Using a framework for surveillance of respiratory infection at all organisational levels throughout the population of Kenya, for the first time temporal-spatial data on four respiratory viruses or virus groups will be coupled to whole-virus genome-sequencing data and data on social contact networks. The aim of this is to predict the most probable transmission routes in the population and to drive mathematical models to be used in exploring the effectiveness of targeted interventions, eg household- or school-based.

Professor Ewan Pearson

University of Dundee

Stratified medicine in type 2 diabetes: insights from the study of drug response

Type 2 diabetes is a major chronic disease that presents a considerable burden to patients and healthcare systems globally. There has been some progress made on understanding the causes of the disease, particularly in unravelling its genetic aetiology, with this knowledge being applied in clinical practice in monogenic diabetes. The field of stratified medicine in diabetes is currently limited to relatively rare forms of monogenic diabetes. Professor Pearson aims to identify new ways to stratify the disease by developing an understanding (clinical, biochemical and genomic) of why some drugs work well in some people with type 2 diabetes but not others. He will also investigate the mechanisms for variation that explain why some patients respond to diabetes drugs and others experience adverse reactions.

Dr Christopher Petkov

Newcastle University

Neuronal mechanisms for extracting communication signals and signalling sequences: from animal models to humans

There is a great need for better treatments for language disorders and more accurate prognosis of language recovery following stroke. To achieve this, an understanding of the cognitive abilities underpinning language and the critical neuronal circuits and pathways involved is required. Dr Petkov's work harnesses the exciting recent development of first-of-their-kind models for understanding two key aspects of human communication: how the brain extracts voice-identity or meaning-related information; and the grammar of communicative sequences. Dr Petkov's group aims to clarify the evolutionarily conserved cognitive abilities that underpin human language, and to bridge the gap between studies in animals, typical humans and language-impaired individuals. This could provide unprecedented scientific insight into the brain pathways and neuronal circuit mechanisms supporting language-related cognitive abilities.

Professor Alison Simmons

University of Oxford

The function of NOD2 in health and Crohn's disease

The intracellular pattern-recognition receptor NOD2 is essential for defence against intracellular microbes, and polymorphisms in NOD2 are associated with the development of the inflammatory bowel disease Crohn's. Professor Simmons has shown that NOD2 activates autophagy to destroy intracellular microbes in a pathway that is defective in Crohn's disease, via the mitochondrial fission protein Drp1. She has three major aims in investigating aspects of NOD2 function: to define signalling to Drp1 with a view to understanding the mechanism of NOD2-mediated Drp1 activation, and to define targets for enhancement of this activity in Crohn's; to understand the influence of NOD2 on antigen presentation and the differences in T-cell responses to different commensal microflora in Crohn's; and to understand the role of NOD2 function in intestinal epithelial cells and how Crohn's-variant NOD2 affects intestinal barrier health.

Professor Kate Storey

University of Dundee

Cellular and molecular mechanisms regulating neuronal differentiation in embryos and adults

Professor Storey is interested in the regulation of neuronal differentiation. She has recently discovered a novel form of cell subdivision, which involves local actin-myosin-mediated abscission of the apical cell membrane in cells poised to undergo neuronal differentiation in chick and mouse embryos. This process also involves the separation of apically positioned centrosome and cilium, and underlies the abrupt loss of apico-basal polarity and cell signalling at the onset of neuronal differentiation. Professor Storey plans to investigate how apical abscission is controlled, how centrosome and cilium separation is regulated and how these processes impacts upon cell signalling. A better understanding of the underlying mechanisms of neuronal differentiation and how these can be manipulated will inform strategies for treatment of neuronal injury and disease.

Professor Christoph Tang

University of Oxford

Bacterial immune evasion

Neisseria meningitidis continues to be a serious pathogen and is the leading cause of meningitis in children. The main aims of Professor Tang's research are to understand the mechanisms that enable Neisseria meningitidis to evade host immunity, the implications of this important pathogen surviving in the human nasopharynx, and subsequent disease in individuals. Professor Tang's approach is to dissect the molecular mechanisms underlying the virulence of this important human pathogen and to analyse the dynamics of carriage of meningococcus and other members of the flora of the human nasopharynx.

Dr Barry Thompson

The Francis Crick Institute

Planar polarity and tissue morphogenesis

How tissue shape is determined during animal development is a major unanswered question in biology. Failure to correctly shape tissues during development can lead to birth defects. The Dachsous-Fat cadherin system of planar cell polarity is essential for determining tissue shape in animals. This system forms long-range gradients across epithelial tissues, which are then interpreted by cells, leading to the orientation of cell movement and division along a particular axis. Dr Thompson aims to identify novel molecules and mechanisms involved in the interpretation of these gradients and the orientation of planar polarity in Drosophila. In doing so he wishes to understand how genetic programmes can organise the shape of a developing tissue.

Dr Abigail Tucker

King's College London

Consequences of the dual origin of the middle ear epithelium on function

The mammalian middle ear is an air-filled space, lined with an epithelium, that houses three small bones called ossicles, which conduct sound from the eardrum to the inner ear. Previously, it was thought that the lining of the middle ear was entirely endoderm-derived. However, Dr Tucker's recent work shows that the lining has a dual origin, as part of the middle ear is lined with neural crest cells that undergo a mesenchymal-to-epithelial transformation. She now aims to understand the normal development of the middle ear – and how defects during development have an impact on the function of the ear – by identifying the signals involved in this mesenchymal-to-epithelial transformation. In addition, she wishes to understand the consequence of the dual origin of the epithelium on susceptibility to ear infection (otitis media) and the development of middle-ear cysts (cholesteatomas), both major problems in the middle ear.

Professor Andrew Wilkie

University of Oxford

Mutations in malformation and disease

Professor Wilkie's research focuses on the mutational processes that cause malformation and disease. By employing high-throughput DNA sequencing, it is now possible to obtain an unbiased inventory of mutations relevant to serious human diseases. Using this information, Professor Wilkie aims to investigate two different but complementary disease areas, in both of which the contributions of single gene mutations are well-established but the inventory of mutations is incomplete. These are craniosynostosis, which is the premature fusion of the cranial sutures, and mutations enriched in normal testes and sperm. One overall goal is to identify all monogenic causes of craniosynostosis, which cause the disease in about one quarter of affected individuals. In addition, pathogenic mutations in sperm will be explored through a novel disease process, termed selfish spermatogonial selection, which has been delineated in Professor Wilkie's laboratory. This will enable the identification of the molecular pathways in the testis that are vulnerable to this process.

Professor Nikolay Zenkin

Newcastle University

Transcription: from catalysis to cellular regulation

Transcription is a critical process in biology, but many of the details underlying key events of the transcription cycle, as well as its regulation, are yet to be uncovered. Professor Zenkin is studying enzymology and the regulation of RNA polymerase – the enzyme that produces the RNA transcript from a DNA template. This research draws on methods from classical biochemistry and molecular biology, as well as some novel and unique experimental systems. In the long term, an understanding of the mechanisms of bacterial transcription may provide the basis for the design of effective antimicrobial agents.

July

Professor Mohan Balasubramanian

University of Warwick

Using a permeabilised cell system and cell physiology to understand cytokinetic actomyosin ring constriction

Professor Balasubramanian's research focuses on understanding eukaryotic cytokinesis mechanisms. Cell division involves an actomyosin-based contractile ring – containing the contractile proteins actin and myosin – which constricts following chromosome segregation to divide one cell into two. However, very little is known about the mechanism of ring constriction and force generation. Professor Balasubramanian intends to research how the actomyosin ring constricts and generates force, and what role myosin II plays in this process. In addition, he aims to establish whether force-generation mechanisms independent of myosin II are involved in actomyosin ring constriction and cell division. Furthermore, he intends to investigate what mechanisms ensure that actomyosin ring constriction is initiated only after segregation of chromosomes. Because actomyosin contractility is central to numerous cellular processes, ranging from wound healing and cell migration to asymmetric cell division and stem cell development, this work will potentially have an impact on a broad range of fields.

Professor Michael Ferguson

University of Dundee

Protein glycosylation in trypanosomes: defining and exploiting a biological system

Professor Ferguson works on glycoprotein structure and biosynthesis in parasites, particularly Trypanosoma brucei, the causative agent of human African sleeping sickness. As part of their strategy to survive inside parasitised hosts, the trypanosomes depend on a coat of surface glycoproteins (proteins with sugar chains attached). Glycoproteins perform many vital functions for the parasites with respect to their infectivity and survival in hosts. These include nutrient uptake, endosome/lysosome function, flagellar adhesion and, above all, hiding themselves from the hosts' immune systems. Professor Ferguson plans to provide a complete understanding of the range of glycoprotein structures made by Trypanosoma brucei and to use the findings as a road map to define the biosynthetic machinery that allows the parasite to assemble them. This knowledge will help identify potential drug targets for translation into drug discovery for sleeping sickness and related parasitic infections.

Professor Frederic Geissmann

King's College London

AMADEUS

Professor Geissmann will seek to understand the role that macrophages play in homeostasis, with a particular focus on their role in metabolic diseases such as type 2 diabetes, cardiovascular diseases and inflammatory diseases. The mechanisms underlying the role of macrophages are incompletely understood, in part due to the heterogeneity of macrophages in vivo. One of Professor Geissmann’s aims will be to understand the functional differences between the myb-dependent and myb-independent macrophage lineages, the latter having been described by him in 2012. He will analyse the contribution of these two lineages to inflammation and foam cell formation using mouse models, and undertake genetic analyses of macrophage responses to a lipid-rich diet using Drosophila.

Professor Neil Gow

University of Aberdeen

Making and breaking the cell walls of fungal pathogens

The cell wall of fungal pathogens determines their pathobiology and immunological signatures. It is a target for chemotherapies and immunotherapies because the major cell wall components are essential and fungal-specific. Professor Gow wishes to understand how the cell wall is assembled and how it is recognised by the immune system. He will investigate key assembly processes and functions of the extended gene families that articulate the cell wall, and deploy novel screens, phenotyping methods and in vitro synthetic biology approaches to dissect the functions of important genes. The programme will also define the chemical structure of cell wall molecules that stimulate, attenuate and imprint the innate and adaptive immune responses. Host and pathogen functional analysis tools will be used to study the immunologically relevant cell wall glycoconjugates. These complementary approaches should advance our understanding of therapeutically tractable targets of the cell wall and will inform the design of new therapeutics and diagnostics.

Professor Erhard Hohenester

Imperial College London

Molecular mechanisms of laminin function in health and disease

Laminins are the major cell-adhesive proteins of basement membranes, the archetypal form of extracellular matrix that is required for tissue formation. Genetic defects in laminins and their cellular receptors cause serious skin blistering diseases, muscular dystrophies and kidney disorders. Yet three decades after the discovery of laminins, we still lack a mechanistic understanding of their iconic functions: polymerisation and cell adhesion. Professor Hohenester’s research aims to address these important unresolved questions through a combination of structure determination and biochemical validation. A better understanding of the molecular mechanism of laminin binding to integrins should aid in the development of new reagents for tissue engineering and stem cell culturing.

Professor Vassilis Koronakis

University of Cambridge

Towards a high-definition view of cytoskeleton remodelling by the bacterial pathogen Salmonella

Professor Koronakis is fascinated with molecular events at biological cell membranes, encompassing the structure and function of bacterial multidrug efflux pumps, and the action of bacterial effectors that seize control of host cells to force pathogen invasion. He aims to study mammalian cell-membrane signalling pathways that are vital to the control of cytoskeleton remodelling in health and infectious disease. He will combine his innovative experimental approach to study membrane signalling platforms in vitro, with his work showing how effectors of the pathogen Salmonella subvert regulatory control of the host cell cytoskeleton. This will focus on the WAVE regulatory complex, one of the cell’s key regulators of actin assembly and cell shape, and how it is controlled by cooperating Arf and Rac GTPases. This fusion of biochemistry and cell biology promises a greater understanding of key signalling processes in our cells, and new insights into how bacteria establish infection.

Dr Peter Magill

University of Oxford

Functional dichotomy in the external globus pallidus

The external globus pallidus (GPe) is a key component of the basal ganglia, a network of brain regions critical for motor control and the learning of routine behaviours. It has long been thought that the neurons of the GPe are a relatively homogenous population, but recent evidence suggests that it is instead made up of dichotomous neuronal groups. Dr Magill will address the necessity for and nature of this dichotomy in the GPe. In elucidating the substrates for GPe neuron specialisation at different scales of function, he aims to provide explanations in the context of whole-brain function and behaviour.

Professor Mala Maini

UCL

Immunopathogenesis and immunotherapy of viral hepatitis

Hepatitis B virus (HBV) remains one of the most frequent causes of death worldwide, resulting in around 600,000 deaths annually from liver cirrhosis and hepatocellular carcinoma. Professor Maini has recently elucidated new pathways by which HBV exploits the tolerogenic hepatic environment to subvert antiviral immunity and promote liver disease. The objective is to build on this work by defining key molecular mechanisms that can be blocked in order to develop novel immunotherapeutic approaches to treat chronic HBV infection. Professor Maini has three interrelated aims: to investigate the capacity of hepatic antigen presenting cells to tolerise T cells; to explore the pathogenic and protective roles of NK cells in the liver; and to develop approaches to promote the survival and function of HBV-specific T cells generated by vaccination or immunotherapy. 

Professor Gilean McVean

University of Oxford

The genetic analysis of populations

Professor McVean's research uses patterns of genetic variation among individuals to answer questions about fundamental biological processes, the nature of evolutionary processes, and the link between genetic variation and an organism's observable characteristics or detectable traits. His research aims to develop statistical and computational tools to integrate de novo sequence assembly and multiple reference sequences to best characterise the genome sequence(s) of an individual or of diverse species (such as malarial parasites). These tools will also be used to define key genomic regions (such as the HLA region) from human sequencing data and to reliably identify diverse genome-changing events from whole-genome sequence data of individuals in extended pedigrees. The genetic structure of the HLA region in different populations will be assessed to explore how variation influences the immune response to, and risk of, infectious and autoimmune diseases.

Professor Markus Müschen

University of Cambridge

Negative feedback and oncogene signalling in leukaemia

Tyrosine kinase inhibitors (TKIs), used against cancer-promoting (oncogenic) tyrosine kinases, have created a new era of treatment for patients with leukaemia and solid tumours. Despite their clinical success in chronic myeloid leukaemia, TKI resistance is a common outcome in almost all other malignancies. Research has uncovered an unexpected dependence of tumour cells on negative feedback regulation of signalling pathways downstream of oncogenic tyrosine kinases. Professor Müschen aims to build a fundamental understanding of: why tyrosine-kinase-driven cancer cells are uniquely sensitive to loss of negative feedback; whether tyrosine-kinase-driven cancer cells can only thrive within the limits of a 'comfort zone' of oncogene signalling, with either attenuation (TKI) or hyperactivation (blockade of feedback) leading to cell death; and how ablation of negative feedback mechanistically leads to cell death. He then aims to leverage this information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and inhibitors of feedback.

Professors Richard Randall and Steve Goodbourn

University of St Andrews, St George's, University of London

The interaction of paramyxoviruses with the interferon system

The interferon (IFN) system is a major component of vertebrate innate antiviral immunity. It is so powerful that most (if not all) viruses have evolved IFN antagonists. Whilst there has been an explosion in our knowledge of this subject in the last 10–15 years, there are still many unanswered questions about how viruses interact with the system. Professors Goodbourn and Randall aim to build up a comprehensive understanding of this interaction by focusing on paramyxoviruses, an important group of human and animal viruses that includes measles, mumps, parainfluenza and Newcastle disease viruses. Their studies will investigate: how paramyxovirus infections trigger IFN production; whether overstimulation of the system (and other innate responses) exacerbates disease processes; how IFN controls paramyxovirus infections and influences virus host range, pathogenicity and persistence; and the potential application of their findings to improve the control of virus diseases.

Dr Jonathan Roiser

UCL

Neural and cognitive processes in depression

Depression is a debilitating illness and represents a major public health problem, with a heavy economic and social burden. Dr Roiser will use neurochemical, neuroimaging and behavioural techniques to understand the cognitive and neural mechanisms underlying depression, which his previous work suggests exist prior to the onset of symptoms and independent of medication effects. Dr Roiser aims to examine how abnormal processing of positive outcomes ('rewards') and negative outcomes (‘punishments’) contributes to particular depressive symptoms, whether this processing is also abnormal before and after an episode of depression, and how it is affected by levels of the brain chemical dopamine. His long-term goal is to provide a testable neuroscientific account of the brain mechanisms underlying depression. In the long term this approach has the potential to improve patient outcomes by moving away from a descriptive level of diagnosis towards a mechanistic approach to classification and treatment.

Professor Colin Taylor

University of Cambridge

Spatial dynamics of receptor-regulated calcium signalling

Professor Taylor's research will investigate calcium signalling, with a particular focus on the structure and behaviour of intracellular inositol trisphosphate receptors. The key question to be addressed is how dynamic organelles and proteins mediate communication between extracellular stimuli and the calcium signals that regulate many cellular activities. These signalling pathways must be specific and sensitive and respond with appropriate speed. A handful of diffusible messengers, including cAMP, calcium and inositol trisphosphate, selectively transmit information from G-protein-coupled receptors (GPCRs), which are activated by diverse extracellular stimuli, to numerous cellular responses. Inositol trisphosphate receptors respond to many of these messengers, generating calcium signals that regulate cellular activity. Defining the dynamic architecture of these signalling pathways is essential to understanding how specificity is maintained as information passes speedily from GPCRs to responses, and to identifying drug targets that might disrupt this communication.

Professor Anton van der Merwe

University of Oxford

Immune recognition by non-catalytic tyrosine-phosphorylated receptors

Professor van der Merwe's research aims to increase our understanding of the molecular and biophysical rules governing recognition by leukocyte receptors, a process that underpins immune responses. He has generated important biophysical data on the interactions that occur between T-cell antigen receptors (TCRs) and their surface-anchored ligands, and has demonstrated that the sizes of the molecules involved in the formation of the immunological synapse play a key role in the resulting signalling outcome. This has led him to propose a novel model of TCR triggering called the kinetic-segregation (K-S) model. Recently he has proposed that other leukocyte non-catalytic tyrosine-phosphorylated receptors (NTRs) are also triggered by the K-S mechanism. Professor van der Merwe will now address three main aims: to determine the mechanism of NTR triggering upon ligand binding; to explore how NTRs integrate their signals with each other and with other receptors; and to elucidate the mechanisms driving, and functional consequences of, NTR aggregation into clusters.

Professor César Victora

Federal University of Pelotas, Brazil

Global observatory of trends and inequalities in child health and nutrition

Expanding on his experience monitoring inequalities in reproductive, maternal, newborn and child health in low- and middle-income countries, Professor Victora will build up a global data platform on health inequalities to address important scientific questions with direct practical implications for country- and global-level decision makers. He aims to systematically analyse levels and trends in population subgroups, with a focus on maternal and child health and nutrition. Specifically, he will examine the monitoring of child health indicators, interpretation and evaluation of recent trends in health and nutrition, develop forecasting of long-term consequences on child health and nutrition, and investigate how findings can be rapidly and effectively disseminated to promote evidence-based decision-making.

Professor Waldemar Vollmer

Newcastle University

Bacterial cell wall synthesis and degradation

Professor Vollmer studies the structure and biosynthesis of the bacterial cell wall that protects the cell from bursting due to internal osmotic pressure, and that maintains the cell's specific shape (spherical, rod-shape, helical, etc). Bacterial cell wall synthesis is targeted by important classes of antibiotics, such as the beta-lactams and glycopeptides. Little is known about how bacteria enlarge their cell wall when they are growing and dividing. This research aims to decipher the molecular mechanisms of cell wall growth in Gram-negative bacteria, which have an outer membrane, including the model bacterium Escherichia coli and important pathogens like Pseudomonas aeruginosa and Helicobacter pylori. Professor Vollmer will study the interactions and activities of cell wall synthesising and degrading enzymes, which presumably form dynamic multi-enzyme complexes catalysing cell wall growth. This could lead to new strategies for interfering with bacterial cell wall synthesis, with the potential for the development of novel antibiotics.

April

Professor Luis Aragon

Imperial College London

Functional dissection of mitotic chromatin

The compaction of chromosomes as cells enter mitosis is probably the most iconic process of dividing cells and represents one of the most fundamental biological processes, yet it is poorly understood. Recent work from Professor Aragon demonstrated that minichromosomes in yeast cells undergo a change characterised by an overwinding of the DNA double helix that is mediated by the condensin complex as chromosomes are compacted. Since nucleosomes impose underwinding on DNA, the observation implies that the distribution and/or conformation of nucleosomes must be altered during mitosis. This realisation provides a radical departure from the view that mitotic nucleosomes are a passive factor during chromosome assembly. Professor Aragon is aiming to investigate the nature and functional role of the histone component of mitotic chromosomes and to uncover the mechanisms by which histones contribute to chromosome condensation.

Dr Jake Baum

Imperial College London

The cellular and molecular mechanics of malaria parasite invasion of the human erythrocyte

Dr Baum's programme of research aims to address key questions in understanding how malaria parasites (Plasmodium species) invade the red blood cell – a critical step in the pathogenesis of malaria disease. The focus of the programme is aimed at every level of investigation, from atomic resolution of the parasite motor and single-molecule biophysical dissection of parasite motor force, to fixed and live imaging of parasite cells on the move. Dr Baum will be combining each of these approaches with comparative Plasmodium biology and, critically, inclusion of the host erythrocyte cell biology, towards the ultimate goal of understanding key events in parasite invasion and the identification of weaknesses that can be targeted to stop it.

Professor Jorge Ferrer

Imperial College London

Understanding regulatory variation in human diabetes

It has recently become apparent that a major fraction of the human genome contains functional regulatory elements. Several studies have demonstrated that sequence variation in noncoding genomic elements can cause Mendelian disorders, and it is widely thought that these noncoding elements are critically important for susceptibility to common complex diseases. Professor Ferrer aims to provide tools to understand how noncoding variants disrupt regulatory functions that cause Mendelian diabetes or type 2 diabetes susceptibility. He will also aim to exploit human genetics to discover novel genome regulatory mechanisms, in analogy to how genetics has revealed unanticipated protein functions underlying beta-cell development and function.

Professor Matthew Freeman

University of Oxford

The control of signalling by members of the rhomboid-like superfamily

Professor Freeman plans to investigate how intercellular signalling is controlled in order to regulate nearly every facet of human physiology. Professor Freeman and his team have recently discovered that proteins of the rhomboid-like superfamily (polytopic membrane proteins related to rhomboid intramembrane proteases, most of which, however, lack protease active sites) act as regulatory adapters to control the fate of growth factors and cytokines, as they are trafficked through the cell. He will examine the molecular and cellular mechanisms by which rhomboid-like proteins determine the fate of signalling proteins, discover how rhomboid-like proteins are influenced by physiological cues, and determine their physiological significance and relevance to human disease. The further understanding of these rhomboid-like proteins may lead to the development of future therapeutic strategies.

Professor Sir John Gurdon

University of Cambridge

Mechanisms for the reprogramming of somatic cell nuclei by eggs and oocytes

Eggs have a remarkable ability to rejuvenate the nucleus of a differentiated (or adult) cell to provide a source of normal embryonic stem cells. Such cells have enormous potential for making disease-specific cultured cells for drug testing and possibly for cell replacement therapy. Nuclear transfer to eggs and transcription-factor-induced pluripotency are routes by which this rejuvenation of differentiated cells, and hence somatic cell reprogramming, can be achieved. Professor Gurdon will investigate which natural components of eggs and oocytes can achieve nuclear reprogramming and how differentiated cells resist reprogramming. It is hoped that examining the mechanisms by which differentiated cells are stable and resist reprogramming will help to explain the processes that, when defective, can lead to disease or cancer.

Dr Lindsay Hall

University of East Anglia

Role of early-life gut microbiota in colonisation resistance development

Complex microbial communities (microbiota) colonise the body after birth. These beneficial bacteria shape immune defence, limiting infection by gut pathogens through a process of colonisation resistance. However, disturbances such as caesarian sections and antibiotic exposure in early colonisation events can lead to increased susceptibility to pathogens, as well as allergic and chronic inflammatory diseases in later life. Dr Hall will work on building our knowledge of the contribution of specific bacterial species during early-life development, and how microbiota disturbances increase susceptibility to gut infection, focusing on bifidobacteria. The goals are to understand the effects of bifidobacteria on critical colonisation resistance, the impacts of antibiotic-induced disturbances, and the potential for restoring a disturbed early-life microbiota to control gut infection, for use in infectious-disease settings.

Dr Matthew Higgins

University of Oxford

Structural studies of host-parasite interactions at the heart of malaria pathogenicity

Proteins on the surface of the malaria parasite are at the front line of its battle with the host. Dr Higgins's project will use the latest tools to determine structures of protein-ligand complexes involved in red blood cell invasion and placental sequestration in pregnancy-associated malaria. Structural studies will allow mapping of polymorphisms onto molecular surfaces while identifying conserved binding sites and inhibitory epitopes on which to focus. An insight into the molecular structure of key malaria surface proteins will guide design of future vaccine components.

Dr Frederick Livesey

University of Cambridge

Human stem cell models of Alzheimer's disease

Dementia is a major healthcare challenge that currently affects about 36 million people worldwide. Alzheimer's disease (AD) is the most common form of dementia, accounting for over 60 per cent of cases, yet there are currently no licensed drugs that modify the course of the disease. Dr Livesey plans to build on his previous work, which led to the development of stem cell models of AD, to generate insights into AD initiation, progression and therapeutic intervention. Specifically, he will investigate how AD progresses and spreads through the human nervous system, and how AD affects neuronal function at the synapse and network level. He will also study AD-associated genetic variants and how these contribute to disease initiation and progression in sporadic, late-onset AD. By examining the causes and mechanisms of AD initiation and progression, it is hoped that these can be reversed and that new therapeutic interventions can be developed.

Dr Andrew McKenzie

University of Cambridge

Innate lymphoid cells in immunity and disease

Following the recent discovery of innate lymphoid cells (ILCs), it was determined that these cells are critical regulators of protective immunity against parasitic helminths and bacteria and also in autoimmune disorders. Dr McKenzie aims to investigate the biological roles of ILCs and to elucidate their developmental relationships within the lymphoid lineage and their functional roles in protective immunity and disease. The aim is to build on existing knowledge of type 1 and type 2 disease models, and their dissection using molecular genetics in mice, to provide new insight into these pathways and identify potential therapeutic targets.

Dr Jack Mellor

University of Bristol

The role of acetylcholine in hippocampal function

The mechanisms by which the neurotransmitter acetylcholine enhances cognition are not fully understood. Dr Mellor will be working towards defining the cellular, synaptic and network effects of acetylcholine in the hippocampus and determining its role in cognition. He will focus on which acetylcholine receptors regulate synaptic plasticity and neural network activity using a multidisciplinary approach. The aim is to define ways to pharmacologically modulate the hippocampal network.

Dr Nicholas Morton

University of Edinburgh

Functional characterisation of the novel adipocyte lean gene thiosulphate sulphurtransferase: developing next-generation obesity therapeutics

Obesity is a major global health problem. Its chronic disease complications (type 2 diabetes, hypertension, atherosclerosis and certain cancers) are the major causes of morbidity and mortality in developed and, increasingly, developing countries. Dr Morton’s vision is that genes promoting healthy leanness in the face of genetic and intense environmental obesity-causing pressures represent important biology and an untapped source for anti-obesity therapeutics. He has identified the enzyme thiosulphate sulphurtransferase (TST) as one possible candidate for driving healthy leanness. Dr Morton’s work will investigate the mechanism of action of TST. He will specifically test the hypothesis that TST augments mitochondrial function, reduces mitochondrial oxidative/metabolic stresses and thereby improves adipocyte function and release of anti-diabetic adipokines. It is hoped that by understanding the role of TST, it may be exploited to ultimately treat obesity and its related metabolic problems.

Professor Jeffrey Pollard

University of Edinburgh

The metastatic cascade: macrophages lead the way

In breast cancer, the survival rate of women with metastatic disease has not changed for 30 years, indicating the need for different treatment strategies. While research has largely focused on tumour cells, it has become apparent that, in tumour progression to malignancy, progressive modification of the stromal microenvironment is as important as the changes in the tumour cells themselves. The aim of Professor Pollard’s research is to define the molecular basis of how macrophages promote tumour progression to malignancy. Specifically, he will investigate how macrophages stimulate angiogenesis, promotion of tumour cell invasion and intravasation, suppression of anti-tumour immune responses, and promotion of extravasation at metastatic sites and their subsequent tumour cell establishment and persistent growth. It is hoped that this research will identify new pathways and targets for therapeutic intervention in human breast cancers.

Professor Barry Potter

University of Bath

Chemical biology of cellular signalling using polyphosphate messengers

Different cells can communicate via chemical messengers, such as hormones and neurotransmitters, and the malfunction of cell-signalling pathways often underlies disease. Such 'first messengers' generally interact with a cell surface receptor, and small-molecule 'second messengers' subsequently carry this signal to internal effector proteins to coordinate a response. Professor Potter will use the techniques of chemical biology, employing synthetic and biological chemistry, to explore the application of tailored synthetic signalling tools in investigative biology. His prime focus is on messengers possessing multiple phosphate groups that dynamically mobilise cellular calcium, such as the cyclitol polyphosphate IP3, and also on newer signalling nucleotides such as cADPR, NAADP and ADPR, and the enigmatic higher inositol polyphosphates. Designing chemical tools for the modulation of these polyphosphates by changing molecular structure, in concert with other interdisciplinary techniques and as part of a process informed by structural biology, will provide both targeted tools for the interrogation of cell-signalling mechanisms and early leads for potential drug candidates.

Dr Jan Rehwinkel

University of Oxford

Cytosolic DNA sensing in infection and autoimmunity

Dr Rehwinkel's programme of research aims to further our understanding of cytosolic DNA detection by the host immune system. Cytosolic DNA detection is important not only during many bacterial and viral infections, but also in autoimmune and autoinflammatory diseases and DNA vaccination. However, the signalling pathways that detect DNA in the cytosol and in particular the DNA sensors triggered by cytosolic DNA remain unknown or incompletely understood. Dr Rehwinkel plans to identify cytosolic DNA sensors and their downstream pathways, establish new models for studying DNA sensors, and define the role of cytosolic DNA sensing during autoinflammation and infection.

Professor Matthew Rushworth

University of Oxford

Neural mechanisms for foraging in an uncertain environment

Professor Rushworth's research is motivated by the idea that some aspects of human decision-making may best be understood using principles from animal foraging behaviour. To test this 'ecological' model, he will employ a range of novel tasks that seek to understand how humans identify what options are available in the environment and how their choices are guided by contextual factors (eg short- versus long-term goals). To understand which brain regions are involved in these processes, Professor Rushworth will combine computational modelling with functional magnetic resonance imaging (fMRI). He will also use transcranial magnetic stimulation to gain insight into how disrupting activity in parts of the decision-making network influences activity in other regions.

Professor Brigitta Stockinger

The Francis Crick Institute

Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor recently shown to play an important role in the immune system, although mechanistic insight is limited. Professor Stockinger plans to investigate the physiological functions of the AhR in the immune system. The programme of work includes: identifying protein interactions with AhR in different cell types and immunological conditions using AhR-FTAP mice; investigating the physiological regulation of AhR signalling via metabolic enzymes; analysing mice with cell-type-specific AhR deletions in order to identify cell-intrinsic consequences of defective AhR signalling; and testing the hypothesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barrier sites.

Dr Jessica Strid

Imperial College London

Lymphoid stress-surveillance – linking tumour immunesurveillance and atopy

The overarching aim of Dr Strid’s programme of work is to characterise and explore lymphoid stress-surveillance (LSS). Described by Dr Strid, this is the activation of local intraepithelial lymphocytes, by physico-chemical tissue damage, that in turn initiates local and systemic Th2 and IgE responses as well as anti-tumour immunity. Key goals of the research are to investigate fundamental aspects of LSS and to determine the role of early LSS-induced Th2 immunity and IgE antibodies in epithelial dysregulation and carcinogenesis. The results will shed new light on the afferent induction of Th2 immunity and will further our understanding of the biological relationship between allergy and cancer.

Professor Sivaramesh Wigneshweraraj

Imperial College London

Non-bacterial regulators of bacterial transcription

The widespread global emergence of bacteria resistant to antibiotics necessitates research into novel antibacterial drugs and drug targets. Bacteriophages, viruses that infect and destroy bacteria, have evolved numerous ways to arrest essential bacterial processes such as DNA transcription and replication, in order to successfully take over the bacterial host for bacteriophage reproduction. The methods employed by bacteriophages represent a new toolbox to inform and inspire novel antibacterial drug and drug target discovery. Professor Wigneshweraraj will focus on research into bacteriophage-derived inhibitors of bacterial RNA polymerase, the enzyme responsible for all RNA synthesis in bacteria.

Professor John Wood

University College London

Peripheral pain pathways

There is a clinical need for a better understanding of pain in order to develop new drugs. Professor Wood has shown previously that different sets of sensory neurons evoke distinct pain sensations. During this Award, he will use a genetic approach and employ novel transgenic mice to define the sets of peripheral sensory neurons responsible for distinct pain sensations and to investigate how these neurons transmit information to the central nervous system. His aim is to identify the mechanisms and molecules associated with distinct pain sensations, focusing on mechanical and cold allodynia and visceral pain. He will also investigate the contribution of sensory neurons, normally associated with innocuous sensations, to pain sensations in neuropathic pain states.

2012

November

Professor Charles Bangham

Imperial College London

Regulation of retroviral latency in the human genome

Professor Bangham’s programme of research aims to understand the regulation of retroviral latency and expression - a problem of central importance in natural retrovirus infections such as HIV-1 and human T-lymphotropic virus type 1 (HTLV-1) and in gene therapy with retroviral vectors. The key goal is to identify the mechanisms by which HTLV-1 regulates its latency and so persists in the face of a strong host immune response, causing fatal and disabling diseases for which there is currently no effective treatment. Professor Bangham will exploit recent exciting discoveries by his team, and the unique advantages of HTLV-1 infection, to answer these fundamental questions in natural HTLV-1 infection and in humans treated with newly developed lentiviral gene therapy vectors. Using state-of-the-art techniques that his group has developed recently, comprising novel high-throughput mapping and quantification of proviral integration sites in vivo and mechanistic experiments in vitro, these studies will have both scientific and clinical significance in pathogenic human retroviral infections and in the rapidly developing field of gene therapy.

Dr Andrew Carter

MRC Laboratory for Molecular Biology, Cambridge

Transport of cargo by cytoplasmic dynein

The size of eukaryotic cells and the crowded nature of their cytoplasm mean that they rely on active transport by motor proteins to move components around. Dr Carter studies cytoplasmic dynein, a poorly-understood complex of proteins that carries out almost all the minus-end directed microtubule transport in cells. This includes the movement of membranous cargos, individual mRNAs and proteins. How dynein selects the correct cargo and transports it at the correct time and place and how viruses such as herpes and rabies hijack this process are currently unclear. Dr Carter aims to uncover the mechanism by which dynein can carry so many different cargos and how such transport is specifically regulated.

Professor Sir Philip Cohen

University of Dundee

Elucidation of molecular mechanisms that activate the MyD88 signalling network

Toll-like receptors (TLRs) are critical components of the innate immune system that are used for defence against bacteria, viruses and other pathogens. Their activation leads to the production of inflammatory mediators that mount responses to fight infection and promote tissue repair. Nearly all TLRs signal via the adaptor protein MyD88, and the goal of Professor Cohen’s research is to elucidate the MyD88 signalling network in molecular detail. This is critical for the development of our understanding of how the production of inflammatory mediators is regulated, why defects in this system lead to immunodeficiency, chronic inflammatory or autoimmune diseases, and to identify pathway components that are targets for therapeutic intervention.

Dr Mark Dillingham

University of Bristol

Double-stranded DNA break resection: from bacterial model systems to human cells

DNA breaks are highly toxic lesions, and failure to repair them correctly is associated with genomic instability leading to cell death, cancer or developmental defects. Repair of double-stranded DNA breaks by homologous recombination is initiated by resection to form a long 3(prime)-terminated ssDNA overhang. It is thought that resection is a two-step process involving structure-specific nucleases, which trim the ends in preparation for more extensive degradation by processive helicases and nucleases. Dr Dillingham is aiming to investigate how human resection factors cooperate to initiate the repair of double-stranded DNA breaks, to characterise the structure and mechanism of the minimal end resection machinery for simple DNA breaks, and to understand how the variety of nucleases involved in resection can process more complex DNA end structures such as ssDNA overhangs.

Professor Lars Fugger

Nuffield Department of Clinical Neurosciences, University of Oxford

Functional genomics in multiple sclerosis

Multiple sclerosis (MS) is a common chronic inflammatory and neurodegenerative disease of the central nervous system. Susceptibility to MS is inherited to a certain extent, but it is not clear which genes confer this risk and how they do so. Professor Fugger will employ a multidisciplinary approach to investigate the genetic association in MS. His goal is to validate candidate genes associated with the disease, clarify their functional roles, and assess how this knowledge can be translated into novel therapeutic approaches to treat MS.

Professor Nick Gay

University of Cambridge

Molecular mechanism of innate signalling in the immune and nervous system

Professor Gay has a long-standing research interest in the Toll-like receptors (TLRs) that alert the innate immune systems of all species, from fruit flies to humans, to the presence of microbial invasion. The novelty of his lab’s contribution has been in characterisation of supra-molecular complexes that are formed during signal transduction by the TLRs. Professor Gay proposes to pursue these studies with respect to the biophysical and structural analysis of the protein interactions within these complexes, as well as using imaging techniques to study the signalling process in vivo. In addition, novel studies will be conducted on the way in which the TLRs synergise with the modular kinase LRRK2 to generate neurotoxicity in the nervous system.

Professor Richard Grencis

University of Manchester

Immunity to whipworm: transforming the paradigm

Professor Grencis is hoping to answer the long-standing question of how gastrointestinal nematodes evade host immunity and survive for prolonged periods of time by studying the whipworm, Trichuris sp., a ubiquitous GI nematode. Previous progress has been hampered by paucity of genomic information, lack of appropriate immunological tools, and lack of tractable experimental murine systems that can readily be translated to human infection. The novel methodologies that are being developed, together with the emerging Trichuris genomic information, will help to identify novel intervention pathways and advance current understanding of the host-parasite relationship, ultimately leading to improvement in human and animal health. The key goals of Professor Grencis's work are to define the genes and their products in both parasite and host that determine successful parasite invasion and survival, to define the host immune dynamics that lead to either host protection or susceptibility, to identify and characterise the key parasite-derived immunomodulatory molecules, and to establish a functional and robust system to study human whipworm.

Dr Angelika Gründling

Imperial College London

Deciphering the nucleotide signalling network of the Gram-positive bacterial pathogen Staphylococcus aureus

Dr Gründling's main aim is to identify proteins and pathways regulated by the nucleotide c-di-AMP and to reveal the molecular bases for its requirement for bacterial growth. Nucleotides are important signalling molecules in all forms of life, and have important roles in bacterial physiology and pathogenesis, often through binding and controlling the function of a specific set of proteins. Current knowledge of their function remains rudimentary. Recent work by Dr Gründling’s team has revealed that c-di-AMP is required for the growth of Staphylococcus aureus and that this nucleotide has a role in the regulation of cell wall integrity in this organism. The plan is to investigate the function of c-di-AMP and additional nucleotides such as pApA, cAMP and ppGpp, with the aim to decipher the interconnections of nucleotide-controlled pathways. A deeper understanding of essential cellular processes in this S. aureus is of great importance, but it is anticipated that the findings will be applicable to a range of bacteria. Ultimately, this research has the potential to provide new targets for the development of alternative strategies to combat infections.

Professor William Harris

University of Cambridge

How to build a retina

Professor Harris is fascinated by how an organ as complex and refined as the brain is made during development. His laboratory focuses on the retina, perhaps the most experimentally tractable part of the brain. The key basic and interrelated questions that form the core of his proposed work are: (1) What mechanisms regulate the appropriate number of neurons generated from a population of retinal progenitor cells that themselves produce variable numbers of descendant neurons? (2) In all vertebrates, retinal cells consist of six main types and more than 50 subtypes. How are these types and subtypes generated in the correct proportions? (3) A conserved feature of retinal development is histogenesis, the relationship between cell birth, cell type and tissue architecture. How is this achieved?

Professor David Horn

University of Dundee

High-throughput decoding of virulence mechanisms in African trypanosomes

Professor Horn works on the African trypanosome, Trypanosoma brucei, which is transmitted among mammalian hosts by the tsetse fly, causing human African trypanosomiasis, or sleeping sickness, and the livestock disease nagana. The molecular mechanisms affecting virulence, antigenic variation, transmission, drug susceptibility and human serum susceptibility have remained largely unknown. Professor Horn’s team have developed RNA interference (RNAi) library screening for exploitation of T. brucei genome sequence data. He wants to exploit the power of the RNAi target sequencing approach to decode the genetic basis of fundamental aspects of T. brucei biology and pathogenesis. The key goals are to characterise the machineries that underpin parasite-drug interactions, evasion from host defence and survival within the mammalian host. The studies promise major advances in our understanding of these key virulence mechanisms.

Professor Susan Lea

University of Oxford

Molecular mechanisms in complement regulation and evasion

Professor Richard Marais

The Paterson Institute for Cancer Research, University of Manchester

Developing personalised medicine for malignant melanoma

Professor Stephen Matthews

Imperial College London

Understanding molecular control of functional amyloidogenesis

Under stress, bacteria switch to a lifestyle that is optimised towards survival, in which they form a community of cells usually attached to a surface, known as a biofilm. By collaborating in a biofilm, bacteria form a safe haven where they are protected from immune system detection and chemical onslaught from antibiotics. Biofilms also cause complications in the provision of clean drinking water, food processing and fouling of manufacturing processes. The formation of a viable biofilm is a highly regulated, complex process in which bacteria secrete a polymeric extracellular matrix. Amyloid fibrils are abundant in bacterial matrix, where they confer structural and organisational integrity due to their unique mechanical properties. Despite the usefulness of amyloids, they are often toxic to a cell when formed at the wrong time or place. Bacteria have devised elegant solutions to control inappropriate amyloid formation, and by using a multidisciplinary structural biology approach, Professor Matthews aims to unravel this extraordinary ability.

Professor James Naismith

University of St Andrews

Transport and polymerisation of bacterial polysaccharides: from cytoplasm to the outside world

Professor Naismith wishes to understand the transport and polymerisation of bacterial polysaccharides, the process by which sugar molecules synthesised within the cell cytoplasm are transported across the cytoplasmic membrane, polymerised and attached to the protein substrates. The first step of the process is coupling of sugar to a lipid carrier by two broad classes of integral membrane proteins that carry out this process. Professor Naismith’s group plans a study of the structures and mechanisms of action of these classes. The next step is flipping across the cytoplasm, carried out by the flippase protein, after which the units are polymerised into a defined length by a polymerase. While the polymer can be attached to a protein or exported or transferred to another receptor, the group will focus research on the attachment of the polymer to protein substrates. Extracellular polysaccharides play a variety of roles in bacteria, especially their role in bacterial pathogenesis. The sugar polymers can help evade the immune system, protect against the immune response or even modulate the immune system.

Professor David Price

Cardiff University

The immunopathogenesis of Epstein-Barr virus-associated malignancies

Professor Nazneen Rahman

Institute of Cancer Research

Genetic and epigenetic investigations of childhood cancer and overgrowth syndromes

The study of childhood cancer and associated syndromes, such as those that result in global or regional overgrowth, has resulted in important insights into basic biological processes and substantial clinical benefits. Professor Rahman’s research has already identified common and rare genetic and epigenetic susceptibility factors for these conditions. However, these only account for a minority of children. Professor Rahman will extend her research to employ genome-wide exomic, genomic and methylation analyses to discover new predisposition factors, together with targeted replication to define prevalence, penetrance, the spectrum of pathogenic mutations and genotype-phenotype associations. The data generated will be integrated to help define the clinically relevant information required for clinical translation of new genes/epigenetic defects, and to produce diagnostic, management and testing protocols for use in clinical practice.

Professor William Richardson

University College London

Transcriptional control of CNS myelination in development and maturity

Professor Richardson studies oligodendrocytes – cells in the CNS that form the insulating myelin sheaths that are necessary for rapid communication between neurons and their targets. Most oligodendrocytes develop early in life but they continue to be produced from their glial precursor cells well into adulthood. There is growing evidence from human brain imaging, as well as from animal models, that adult-born oligodendrocytes and myelin are involved in some forms of learning and memory (eg motor skills learning). In addition, new oligodendrocytes are required for repairing areas of acute myelin damage such as occur in the demyelinating disease multiple sclerosis. Professor Richardson will use his Investigator Award to study the molecular control of myelin development, with the long-term aim of learning how to stimulate normal learning processes or to repair myelin damage. He will focus on transcriptional control, because this is the convergence point of many signalling pathways that together orchestrate the myelination programme.

Professor Polly Roy

London School of Hygiene and Tropical Medicine

Understanding the infection processes of bluetongue virus as a model of complex, non-enveloped orbiviruses: viruses with segmented double-stranded RNA genomes and multilayered capsids

Professor Roy's main aim is to understand how complex, non-enveloped orbiviruses (family Reoviridae) successfully invade host cells, replicate and cause disease, and hence to understand how to better control virus outbreaks. The studies address the most challenging key stages of the orbivirus life cycle: how it breaches the plasma membrane of the host cell to deliver a large capsid into the cytoplasm, how it regulates the release of newly synthesised transcripts from the capsid into the cytoplasm, and how transcription complexes become precisely located at the capsid vertices and, lastly, how newly assembled subviral particles exit from their assembly site to leave the host cell. Together with a reverse genetics system that allows targeted mutations in the viral genome to dissect replication events of these complex capsid viruses, and the latest imaging technologies, Professor Roy will use advanced techniques pioneered in her laboratory: an in vitro cell-free infectious particle assembly system, for a complex dsRNA virus. The use of these hybrid approaches is allowing new findings in the biology of viruses and cells that would not have been possible even a few years ago.

Professor Pauline Schaap

University of Dundee

Molecular mechanisms of encystation and sporulation

Professor Schaap studies the genetically tractable Dictyostelid social amoebas. These have a sporulation phase in their life-cycle which is evolutionarily derived from encystation – a mechanism employed by pathogenic protozoa and which can cause problems, as cysts are resistant to immune clearance, antibiotics and biocides. Professor Schaap will use a Dictyostelid model to investigate the signalling pathways of encystation and explore whether crucial regulatory proteins in these pathways might be suitable targets for the design of drugs to inhibit encystation.

Professor John Schwabe

University of Leicester

The molecular functioning of HDAC:co-repressor complexes

Histone deacetylases (HDACs) are essential enzymes required for human development and homeostasis and they are increasingly recognised as important targets for the treatment of cancer and other diseases, including Alzheimer's. HDACs 1-3 serve as catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes remove acetyl groups from histones, resulting in the condensation of chromatin, which causes gene silencing. Professor Schwabe plans to determine the structures of the four HDAC1 and HDAC3 holo-complexes, in order to define the specificity of their assembly and their role in determining target gene and substrate specificity. He will also be researching the biological role of inositol tetraphosphate in regulating HDAC complexes and the potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides.

Professor Andrew Sewell

Cardiff University

Reducing transplant rejection by mapping the alloreactivity footprints of abundant virus-specific T-cell populations

July

Professor Martin Allday

Imperial College London

Epigenetic reprogramming of B cells in viral persistence, disease pathogenesis and tumour immunosurveillance

Professor Allday aims to understand how latent infection with Epstein-Barr virus (EBV) epigenetically reprograms mature human B cells and their progeny. This involves viral proteins manipulating host polycomb-group proteins to repress the transcription of specific host genes – including at least two tumour suppressors. The goal is to not only determine the role of these processes in EBV biology and EBV-associated cancers but also provide unique insights into the molecular mechanisms underpinning polycomb-group-mediated gene repression and how they can be manipulated by viruses and perhaps other microorganisms.

Professor David Attwell

University College London

The development, plasticity and pathology of myelinated CNS axons

Professor Attwell's lab is interested in the interaction between neurons and glial cells. With this award Professor Attwell will investigate the development, plasticity and pathology of myelinated CNS axons. Myelinated axons form the white matter of the brain and spinal cord. They are generated by a subtype of glia called oligodendrocytes that wrap myelin around axons, which speeds action potential propagation along the axons. However, myelinated axons are poorly understood, and Professor Attwell will address the following questions: (1) How is oligodendrocyte development regulated to set axonal conduction speed? (2) What are the mechanisms of white matter plasticity that may contribute to learning? (3) How is the oligodendrocyte-axonal unit disrupted in pathology? As well as increasing our understanding of myelinated axons, this research will also give insight into potential therapeutic approaches for protecting myelin and promoting myelination in de-/dysmyelinating disorders, such as multiple sclerosis.

Professor Shankar Balasubramanian

University of Cambridge

The chemical biology of the genome and epigenome

Professor Balasubramanian's research exploits chemical approaches to understand the structure, chemistry and function of DNA. His broad goals are to understand the importance of chemical modification of DNA bases, such as 5-methylcytosine and 5-hydroxymethylcytosine, in normal biology and disease states. He will exploit and develop new chemical and analytical approaches for exploring alternative bases in the genome, to include the recent inventions of quantitative sequencing of 5-hydroxymethylcytosine at a single-base resolution and the genome-wide chemical mapping of 5-formylcytosine from his laboratory.

Professor Richard Elliott

University of St Andrews

Molecular analyses of arbovirus-host interactions

Professor Richard Elliott wants to understand the molecular details of arbovirus replication that account for the different outcomes of infection in vertebrate and invertebrate cells. Like other groups of arthropod-transmitted viruses, bunyaviruses are responsible for severe morbidity and mortality throughout the world. They cause diseases ranging from febrile illness and encephalitis to fatal haemorrhagic fevers. The virus transmission cycle involves replication in a blood-feeding arthropod and a vertebrate host. In both hosts the viruses replicate efficiently but with fundamentally different outcomes for the cell: nonlytic in invertebrate cells, leading to a persistent infection, versus lytic in vertebrate cells, leading to cell death. The overall vision is to obtain a comprehensive understanding of the molecular biology of bunyavirus replication that will ultimately lead to new methods of control, prevention or treatment for bunyavirus disease. To achieve this, Professor Elliott plans to determine the functions of different viral components during the replication cycle and to investigate how cells defend themselves against virus infection (and, in turn, how the virus copes with these defences). A major interest is the role of small RNAs in controlling infection. State-of-the-art microscopical techniques will be employed to monitor virus replication in real time, and reverse genetics will be exploited to engineer attenuated viruses with potential as vaccines.

Professor Gerard Graham

University of Glasgow

Dissecting the chemokine basis for the orchestration of the in vivo inflammatory response

Professor Graham's research intends to improve our understanding of how an inflammatory chemokine response is coordinated and regulated. Using cutting-edge genome engineering, his lab will generate mice with silenced inflammatory chemokine receptors. This silencing is reversible to allow the receptors to be selectively switched on in turn, as well as in select combinations, illuminating the role of each receptor in the orchestration of the chemokine-dependent inflammatory response. He also aims to determine the dynamics of receptor expression in the orchestration of tissue-specific in vivo inflammatory responses.

Professor Matthias Merkenschlager

Imperial College London

Genetic approaches to dissect the role of cohesion in gene regulation

Cohesin is a protein complex best known for its role in chromosome biology, but recent work suggests additional functions in gene expression, development and cancer. Research in Professor Merkenschlager's lab demonstrated that cohesin regulates gene expression independently of its canonical functions in the cell cycle. This realisation opened a new perspective on gene regulation, in line with growing awareness of the importance of higher order genome organisation. The aim of his research is to uncover the mechanisms by which cohesin regulates gene expression and eventually suggest approaches to the management of clinical conditions where cohesin function is compromised.

Professor Terence Rabbitts

University of Oxford

Tracing cancer evolution using mouse models

Professor Rabbitts is a molecular biologist who will be using models of cancer progression to determine the changes associated with the development of cancer from initiation to overt cancer. Specifically, he will be comparing which genes are expressed and which proteins are produced as tumours evolve in these different cancer models. These studies will identify new markers for diagnosis and new targets for therapy.

Dr Bénédicte Sanson

University of Cambridge

In vivo mechanisms of collective cell movement and cell sorting

Dr Sanson studies morphogenesis in the Drosophila embryo and is interested in how the action of genes and mechanical forces work together to shape developing tissues. With this award, she will be concentrating her studies on a short window in early development when the embryo’s tissues undergo changes that are common to all bilateral organisms, including humans.

Professor David Sherratt

University of Oxford

Illuminating the in vivo molecular mechanism of bacterial chromosome replication and segregation

Chromosome replication and segregation are critical processes for life but little is known about when, where and how these occur at the single-molecule level. Professor Sherratt will use state-of-the-art live cell imaging, which enables visualisation at the individual protein level of the assembly and action of individual molecular machines that act in bacterial chromosome replication and segregation. He aims to track the progress of a single replication fork from initiation to termination, to visualise the recruitment of recombination-repair proteins to site-specific double-strand breaks and to dissect the molecular mechanism of chromosome segregation.

Dr Benjamin Willcox

University of Birmingham

The molecular basis of gamma delta T cell recognition in health and disease

May

Claudio Alonso

School of Life Sciences, University of Sussex

The molecular regulation of Hox genes during animal development

Dr Alonso is a molecular biologist interested in how the process of animal development is molecularly controlled. More specifically, he studies the regulation of the Hox genes, a family of genes required for the correct head-to-tail patterning of animal bodies. His recent work indicates that RNA regulatory processes are important for Hox expression and function during the formation of the central nervous system (CNS) in Drosophila. He will be pursuing studies to understand more about the molecular mechanisms of Hox RNA regulation and investigate how these might contribute to Hox gene function within the developing CNS.

Dr James Briscoe and Dr Karen Page

The Francis Crick Institute and Department of Mathematics, UCL

Regulatory dynamics of vertebrate neural tube development

This joint Investigator Award will draw on the complementary expertise of Dr Briscoe and Dr Page in the areas of developmental biology and mathematics, respectively. The overall goal of their work is to understand the mechanisms of pattern formation in developing tissues, using the vertebrate neural tube as a model. The researchers will build on their recent studies in the neural tube, which have shed light on how patterns of gene expression are formed in response to external cues, by attempting to reconstitute neural tube development in silico and in vitro.

Professor Raymond Dolan

Wellcome Trust Centre for Neuroimaging, UCL

The neurobiology of motivation in health and disease

Professor Dolan's goal is to understand motivation in terms of the computational processes being undertaken by neural circuits in the brain. He will study this by using behavioural and neuroimaging techniques, in combination with computational models. He aims to determine how motivation impacts on behaviour, addressing how such processes may be altered when the brain is in a psychiatric state (e.g. in clinical depression). Ultimately he hopes to use his findings to refine psychiatric disorder classifications, which will help provide more focused targets for future investigations and for potential treatment options.

Professor Annette Dolphin

Department of Neuroscience, Physiology and Pharmacology, UCL

Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins

Professor Dolphin's research focuses on neuronal voltage-dependent calcium channels, in particular the role of the accessory subunits β and α2δ. Understanding these channels and their accessory subunits is highly relevant to neuropathic pain as both CaV2.2 and α2δ-1 represent important therapeutic targets. In this award, Professor Dolphin will research the interaction of the α2δ subunits with other proteins. Work from her lab has shown that α2δ subunits interact with trafficking proteins. Professor Dolphin therefore aims to examine how this interaction influences the trafficking of α2δ subunits and their associated calcium channels, and whether gabapentinoid drugs can disrupt this interaction. A second aim of her research is to look more broadly at whether α2δ subunits influence other proteins, with a particular focus on other ion channels.

Professor Jeffrey Errington

Institute of Cell and Molecular Biosciences, University of Newcastle

Chromosome segregation and cytokinesis in bacteria: mechanisms and regulation

Professor Jeffrey Errington is investigating the cell cycle, a pivotal process in biology, of which mechanistic details underlying many of the key events are not well understood. The ability to regulate chromosome replication, segregation and cytokinesis is one of the most fundamental processes for organisms as it is crucial for survival, fitness, reproduction and evolutionary success. Professor Errington plans to resolve the molecular details underlying these key events in bacteria, which have the advantage of relatively simple cells and genes and are therefore tractable in experimentation. A better understanding of this fundamental process in bacteria might enable scientists to interfere with essential functions in pathogenic bacteria, which could in turn inform antibiotic design.

Professor Elizabeth Fisher and Dr Victor Tybulewicz

Department of Neurodegenerative Disease, UCL and The Francis Crick Institute

Understanding Down's syndrome phenotypes through innovative mouse genetics

Professor Fisher and Dr Tybulewicz are building on previous Trust funding to extend their successful collaboration with a Joint Investigator Award. They plan to investigate the mechanisms involved in the translation of human chromosome 21 genes into the Down's syndrome phenotype. Down's syndrome is the most common form of intellectual disability, but the phenotype is highly variable and little is known about the mechanisms that determine which features are expressed. Professor Fisher and Dr Tybulewicz will use their award to concentrate on the cellular and molecular mechanisms underlying the cardiac development, learning and memory, and locomotor function deficits associated with the disorder.

Professors Joachim Gross and Gregor Thut

Institute of Neuroscience and Psychology, University of Glasgow

Natural and modulated neural communication: State-dependent decoding and driving of human brain oscillations

Professors Gross and Thut will be working in partnership to understand aspects of rhythmic network activity in the human brain. As part of this research, they plan to develop and use methodologies to decode and change brain communication by means of MEG/EEG and non-invasive brain stimulation. They seek to understand how the oscillatory network activity gives rise to the complexity and efficiency of human behaviour and to explore to what extent this activity can be controlled by brain stimulation in the healthy and diseased brain.

Professors Andrew Hattersley and Sian Ellard

Peninsula Medical School, Universities of Exeter and Plymouth

New insights from neonatal diabetes

Professors Hattersley and Ellard are together investigating the function and development of the human pancreatic beta-cell through genetic, functional, physiological and clinical studies of patients with neonatal diabetes. Neonatal diabetes is a rare monogenic subtype of diabetes that is diagnosed before six months. Their previous work led to hundreds of patients stopping insulin and achieving better control of their diabetes with sulphonylurea tablets. A rapid, comprehensive and international genetic testing service will provide a platform for recruitment and benefit patients throughout the world. They will use new DNA sequencing technology to identify novel genes, then characterise the gene defects using functional and physiological studies in patients.

Professor Ronald Hay

College of Life Sciences, University of Dundee

Determining the role and mechanism of action of the SUMO targeted ubiquitin ligase RNF4 in maintaining genome integrity

RNF4 is a protein that is important for maintaining the stability of the genome in higher eukaryotic cells. Professor Hay is aiming to define the role of RNF4 in the cellular response to DNA damage and to establish the molecular mechanism that is employed by RNF4 to catalyse the transfer of ubiquitin to substrates. Specifically, he will use quantitative proteomics to identify proteins that are targeted by RNF4 in response to genotoxic stress and he will establish how the RNF4-dependent ubiquitination leads to a functional change in protein activity. The impact of DNA-damaging cancer therapies is attenuated by the DNA repair process, so a better understanding of the actions of RNF4 may help in the design of DNA repair inhibitors that could have an enhanced effectiveness against cancer cells.

Professor Mark McCarthy

The Oxford Centre for Diabetes, Endocrinology and Metabolism and the Wellcome Trust Centre for Human Genetics, University of Oxford

Characterising causal alleles for common disease

Professor McCarthy's research focuses on using large-scale genetic and genomic approaches to understand the genetic variants underlying predisposition to type 2 diabetes and those influencing related phenotypes including obesity and glycaemia. His research seeks also to translate gene identification into biological insights and clinical advances. He will aim to define the mechanisms responsible for the pathogenesis of type 2 diabetes by integrating data emerging from large genetic studies in man with emerging insights from the genomic biology of key tissues and physiological studies in man.

Dr Simon Myers

Department of Statistics, University of Oxford

Development of statistical and experimental approaches to understand the roles of recombination and migration in human biology and disease risk

Professor Sussan Nourshargh

William Harvey Research Institute, Queen Mary, University of London

Mode and dynamics of neutrophil transmigration in vivo: mechanisms and implications to pathological inflammation

Neutrophils are a major component of innate immunity and are indispensable for host defence against invading pathogens. As recent evidence indicates a broader role for these cells in inflammation and immunity than conventionally considered, there is a need for better understanding of the mode, mechanisms and implications of neutrophil trafficking in vivo. With this award Professor Nourshargh proposes to investigate how pathological inflammatory insults impact the dynamics of neutrophil-vessel wall interactions and the implications of disrupted modes of neutrophil transmigration on inflammatory disease development and dissemination. By using advanced 4D imaging platforms to analyse neutrophil transmigration, Professor Nourshargh's work aims to unravel previously unexplored cellular and molecular physiological concepts and identify disease-specific phenomena.

Professor Guy Rutter

Section of Cell Biology, Imperial College London

Understanding pancreatic beta cell dysfunction in diabetes

Professor Rutter will exploit findings from recent genome-wide association studies (GWAS) and a family of genes that are strongly and selectively inactivated in healthy beta cells but upregulated in these cells in diabetes. His approach will include combining bioinformatic, in vitro and in vivo analyses in model systems to assess the potential of novel GWAS genes as targets to improve insulin secretion in type 2 diabetes. He will also work towards early translation of his work, through high-throughput platforms to identify both endogenous and small molecule regulators of the best-defined GWAS genes.

Professor Benjamin Simons

Department of Physics, University of Cambridge

Lineage tracing as a strategy to resolve mechanisms of stem cell fate: from development and maintenance to disease and ageing

Professor Simons has a background in condensed matter physics but since 2005 has turned his expertise towards answering fundamental questions in stem cell biology. With this award, he will be using a combination of experimental and theoretical approaches to study how stem cells are regulated in tissue maintenance, development and disease. His work will focus on a wide range of biological systems, including the epidermis, neuroepithelia and gut.

Professor Molly Stevens

Department of Bioengineering and Materials, Imperial College London

Exploring and engineering the cell-material interface for regenerative medicine

Professor Stevens takes the approach of exploring the cell-material interface and then engineering it to deliver a new generation of cell instructive biomaterials. The overall goals of her work are to develop state of the art materials and characterisation approaches so that she can identify subtle phenotypic changes in cell differentiation or biological activity in response to engineered materials implanted in the body. Professor Stevens’ innovation of novel biomaterials that actively interact with the body will contribute to her ultimate aim of the regeneration of failing organs.

Professor Gabriel Waksman

Institute of Structural and Molecular Biology, Birkbeck College and UCL

An integrated study of a bacterial secretion nanomachine

Professor Miles Whittington

University of York

Learning and sleep: a network dynamic approach

Professor Whittington aims to explore the neural brain rhythms associated with sleep and how these may relate to both learning and memory, as well as the pathologies associated with neurological and psychiatric illness. A key question that Professor Whittington will address is how disrupted network dynamics during sleep contribute to learning disability. He will achieve this by combining a variety of techniques from the microscopic to the macroscopic level.

Professor Xiaodong Zhang

Division of Molecular Biosciences, Imperial College London

Structures and mechanisms of key components in the DNA damage response

The fidelity and stability of a cell's DNA are critical for the survival and proper functioning of an organism. There are tens of thousands of DNA damage events every day, and a double-strand break is one of the most severe types that can occur. Consequently, damaged DNA needs to be repaired rapidly as failure to do so can lead to cell death or the development of cancer. As a result, cells have evolved systems to sense, signal and repair this damage. The focus of Professor Zhang's Investigator Award will be using structural biology approaches to provide a mechanistic insight into key steps in the cell’s response to a double-strand break.

February

Professor Francis Barr

University of Oxford

Mechanism and structural analysis of Rab GTPase control systems in normal cells and human disease states

Professor Barr will be studying a family of proteins known as Rab GTPases that regulate many steps in membrane trafficking. Rab GTPases form part of an essential recognition system which gives unique identity to organelle and vesicle membrane surfaces, enabling vesicles to be specifically recognised during transport. Professor Barr will explore how Rab GTPases are involved in membrane trafficking pathways within human cells in both normal and disease states.

Dr John Christodoulou

University College London

Structural biology of protein folding on the ribosome

Dr Christodoulou studies the co-translational folding process, which transforms a nascent polypeptide chain into a fully folded and functional protein as the chain emerges from the ribosome (the protein synthesis machinery in cells). His research will look at the structure and dynamics of nascent proteins during their synthesis, how they interact with the ribosome and molecular chaperones (proteins that aid folding) and how the ribosomal machinery aids trafficking to the correct cellular compartment. This knowledge of how protein three-dimensional structures arise or misfold is important in a range of metabolic, oncological and neurodegenerative conditions.

Professor Harry Gilbert

University of Newcastle

Understanding the contribution of the human microbiota to human health

Professor Gilbert, a carbohydrate biochemist based at Newcastle University, aims to gain a better understanding of the role the human intestinal microbiota - the community of microorganisms resident in our gut – plays in health and disease. Specifically, he will investigate how the uptake and breakdown of dietary glycans – complex carbohydrates such as pectins and starch - contribute to the survival of dominant members of the microbiota in the human large bowel and their ability to modulate our metabolism and our immune system.

Professor Raymond Goldstein

University of Cambridge

Synchronization of cilia

Professor Goldstein's research focuses on cilia, conserved cellular appendages which play an important role in many aspects of life, from transport of fluid in the respiratory tract to signal transduction in the eyes. The coordinated beating of groups of motile cilia is often crucial to their function, and Professor Goldstein will use advanced microscopy, micromanipulation and theoretical modelling to address the mechanism underlying the synchronisation of cilia.

Professor D Grahame Hardie

University of Dundee

Non-canonical pathways for regulation of AMPK

The AMP-activated protein kinase (AMPK) has key roles in the regulation of eukaryotic cell function. Professor Hardie played a major role in uncovering the 'canonical' pathways by which AMPK is activated by energy stress and by calcium ions, but it now also appears to be regulated by other‘non-canonical’ pathways, and the focus of this Investigator Award will be to investigate these. He will study how the pathway is down-regulated in rapidly proliferating cells, how it can monitor cellular glycogen reserves, how it is involved in responses to the commonly used drug aspirin, and how it is activated by DNA-damaging agents. These studies should provide insights into, and may have applications in, both cancer and diabetes.

Professor Paul Martin

University of Bristol

Investigating the links between inflammation and fibrosis during tissue repair

Using a multi-model organism approach, Professor Martin is investigating the cell biology of each step of tissue damage-triggered inflammation: from inflammatory cell recruitment/activation, to the change in fibroblast deposition of collagen that leads to a scar. He will use this cell biology knowledge to identify further mechanistic links between inflammation and scarring, to inform potential therapeutic strategies for blocking fibrosis. A better understanding of the steps leading to the fibrotic process is clinically significant in contexts beyond scarring of skin wounds, as extensive tissue damage-triggered inflammation underlies many human pathologies, including rheumatoid arthritis and liver cirrhosis.

Professor Stephen McMahon

King's College London

Identifying novel pain mediators and mechanisms

Professor McMahon will be examining the sensory neurobiology of chemokines and testing the hypothesis that some of these may function as novel pain mediators. This is important because the identification of new mediators will drive drug development programmes focussing on the amelioration and alleviation of chronic pain.

Professor Daniel Wolpert

University of Cambridge

Computations in sensorimotor control

Professor Wolpert's research will focus on understanding how the brain controls the body for real-world tasks. He will use theoretical, computational and experimental studies to investigate three key components of sensorimotor control: decision making, learning mechanisms and internal representations. He will aim to integrate the models developed for each component into a unifying framework for sensorimotor control.

2011

October

Professor Julian Blow

University of Dundee

Understanding the cellular response to replication inhibition 

Professor Blow will study how cells respond to the inhibition of DNA replication. His goal is to determine whether mutations in cancer cells can make them susceptible to chemotherapeutic drugs that target DNA replication.

Professors William Cookson and Miriam Moffatt

Imperial College London

Genetics and genomics and respiratory disease

Professors Cookson and Moffatt will be using the latest genetic and genomic tools to uncover the basic mechanisms that cause childhood asthma. Asthma is the most common chronic disease of childhood, but its causes remain unknown. Their aim is to translate this knowledge into new treatments for patients with the respiratory disease.

Professor Mark Harris

University of Leeds

Coordinated use of the hepatitis C virus genome during the virus lifecycle

Professor Harris seeks to achieve a comprehensive understanding of key events in the lifecycle of the hepatitis C virus, with the ultimate goal of developing new antivirals. The questions that underpin his vision involve defining in molecular detail the processes by which the virus genome is replicated and packaged into virus particles, and determining how these events are coordinated.

Professor Derek Jones

Cardiff University

Tractometry

Professor Jones will focus on the development and application of tractometry, a non-invasive MRI-based approach to obtaining detailed information about the microstructure of white matter, the connections that carry information between different regions of the brain. Professor Jones believes that this approach will become commonplace in all neuroimaging studies alongside functional imaging of grey matter, where the information is processed, and will be instrumental in advancing our understanding of the brain in health, development and disease.

Dr Steven Kennerley

University College London

Neuronal mechanisms underlying value-based decision-making and action selection

Dr Kennerley will use his award to investigate the neuronal mechanisms supporting optimal learning, decision-making and action selection. He uses sophisticated techniques to record the electrical activity of individual and populations of neurons in the frontal cortex and basal ganglia. His goal is to better understand how the brain evaluates the potential costs and benefits of a decision, and how dysfunction of this evaluative system might lead to neuropsychiatric diseases associated with impaired decision-making.

Dr Peter Lawrence

University of Cambridge

Planar cell polarity and morphogenesis

Cells in epithelial sheets are polarised in the plane of the sheet, as shown by the patterned orientation of mammalian hairs and insect bristles. This fundamental phenomenon, known as planar cell polarity (PCP), is seen across animal and plant development. Dr Lawrence studies PCP in the fruit fly Drosophila, the model system best suited to genetic and molecular analysis. He aims to understand the molecular mechanisms whereby cells read their orientation within an animal or organ and communicate that information to neighbouring cells. The mechanisms use intercellular molecular bridges.

Professor Troy Margrie

MRC National Institute for Medical Research

The function and connectivity of cortical cells and circuits

The wiring and function of cortical circuits underlies brain operation and thus our ability to think, feel and behave. To genuinely understand this process, a detailed knowledge of cell-to-cell connectivity and neuronal network function is required. Professor Margrie aims to generate the first detailed wiring diagram of sensory cortex by combining classic in vivo electrophysiological approaches with two-photon microscopy and rabies-virus-based neuronal tracing methods. By establishing the function of individual cells and identifying the local and long-range circuits in which they operate, he will generate three-dimensional connectivity maps and use them to quantify the function and structure of cortical circuits. This combinatorial approach will then be applied to investigate and quantify the wiring profiles of healthy and diseased brains.

Professor Patrick Maxwell

University College London

Oxygen sensing

A fundamental challenge for complex multicellular organisms such as humans is continuous distribution of sufficient oxygen to all cells throughout the body. As such, oxygen plays a central role in health and disease and changes in oxygenation are critically involved in many disease processes, including myocardial ischaemia, stroke and even cancer tumour behaviour. Professor Maxwell aims to establish how different cells and organisms adapt to changes in oxygenation and whether we can use knowledge of molecular oxygen-sensing pathways to understand and treat disease.

Dr Venki Ramakrishnan

MRC Laboratory of Molecular Biology, Cambridge

Structure and function of ribosomes

Ribosomes are complex structures within cells that use instructions in our genes to synthesise protein chains from individual amino acids, a process known as translation. Dr Ramakrishnan will continue his world-leading work to elucidate the structure and function of the ribosome, in particular studying the mechanism of translation and ribosomal stress response in bacteria, as well as the initiation and termination of translation in eukaryotes (higher organisms, including humans, whose cells contain a nucleus).

Professor Azim Surani

University of Cambridge

Principles and programming of the mammalian germ line

Primordial germ cells, which give rise to eggs and sperm, are the focus of Professor Surani's research. These cells generate totipotency, which allows transmission of genetic and epigenetic information to a new individual and subsequent generations. Professor Surani's studies on mammalian germ cells will aim to elucidate the molecular mechanisms of how germ cells are formed and how they acquire their unique properties, and to inform the application of this knowledge towards manipulation of normal and aberrant cell fates.

Professor Henning Walczak

Imperial College London

Studies of linear ubiquitin and different modes of cell death induction by TNF family members in aetiology and treatment of autoimmunity

Professor Walczak's work examines the modulation of cell death in the context of experimental and clinical autoimmunity. With this award he will investigate the control of different forms of cell death and the determinants of whether cell death leads to inflammation or autoimmunity, through an analysis of the different cell death modalities induced by members of the TNF cytokine family and the role linear ubiquitination plays in determining this.

Professor Fiona Watt

Centre for Stem Cells and Regenerative Medicine, King's College London

Reciprocal signalling between epidermal stem cells and their neighbours

Using mammalian skin as an experimental model, Professor Watt is identifying the intrinsic and extrinsic signals that regulate stem cell behaviour in adult tissues, and thereby uncovering strategies to treat disease. The focus of her award is reciprocal signalling between epidermal stem cells and cells in the underlying connective tissue, the dermis. Relationships between different dermal cell populations will be elucidated as well as how these cells communicate with epidermal stem cells.

Dr Finn Werner

University College London

An integrated study of RNA polymerase transcription

RNA polymerase (RNAP) facilitates important regulatory events in the cell through its pivotal role in transcription. Dr Werner aims to characterise RNAP and its interactions with partner molecules in a group of organisms called Archaea, which is emerging as a versatile model system owing to the stability of their proteins and simplicity of their genetics, genomes and regulatory networks. Investigating the molecular mechanisms of transcription is important because it expands our knowledge of fundamental processes that are essential to all life. Illuminating structure-function relationships of RNAPs is also needed to rationalise the mechanisms of drug action, and thus holds great promise for the development of novel improved drugs to combat agents of infectious diseases by interfering with transcription.

Professor Rose Zamoyska

University of Edinburgh

Mechanisms that regulate T cell responses and their failure in autoimmunity

Autoimmune diseases are those in which dysregulation of immunity leads to attack of body tissues. Professor Zamoyska will examine the cell-signalling events that underpin the regulation of autoimmune T cells, with particular focus on PTPN22, a gene that has been implicated in several human autoimmune diseases.

May 

Professor Jürg Bähler

University College London

Non-coding RNA (ncRNA) function in genome regulation and cell maintenance

Genome sequences often contain large non-coding regions, also known as 'gene deserts', which produce ncRNAs. Genetic variations associated with complex disorders frequently map to these areas, raising important questions about how much genetic information is transacted by ncRNAs. Professor Bähler will investigate the role of such ncRNAs in cellular function and ageing, using fission yeast (Schizosaccharomyces pombe) as a model system. He aims to explore the ability of these ncRNAs to tune gene expression, mediate gene-environment interactions, and generate phenotypic variation and plasticity.

Professor Juan Burrone

King's College London

Homeostatic plasticity: from synapses to the axon initial segment

Our bodies tightly regulate many aspects of their inner physiology, such as temperature, blood pressure and glucose levels. This process, known as homeostasis, serves to keep certain key physiological events constant in the face of a continually changing environment. Neuronal homeostasis is known to play an important role in the stabilisation of brain function. However, little is known about the mechanisms that control it, the site in the neuron at which it takes place and even the levels of activity a neuron senses as abnormal. Professor Burrone aims to tackle these questions by using techniques that provide fine control of the electrical activity of neurons by means of light. This non-invasive approach will enable the study of neuronal homeostasis and could uncover potential new targets for epilepsy treatment.

Professor Javier Caceres

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh

RNA-binding proteins in health and disease

Professor Caceres will be studying the roles of RNA-binding proteins involved in gene expression, a process that leads to the production of proteins and small RNA products through transcription, RNA splicing and translation. As there is a wide variety of RNA-binding proteins, each with a unique binding activity to RNA, these proteins have a profound effect on gene expression networks in cells, making them highly significant to normal and disease-related biology. The work will contribute to a better understanding of the fundamental biological processes involved in gene expression.

Professor Matteo Carandini

University College London

Integration of internal and external signals in sensory cortex (joint award with Professor Harris)

Professor Carandini is interested in understanding how the brain processes visual information. To do this he records the brain activity of mice while they navigate a virtual environment, and looks at the activity of both single and multiple neurons in populations. During his award he will be seeking, alongside Professor Harris, to understand how the brain integrates signals from multiple sensory streams and both sensory and non-sensory modalities.

Professor V Krishna Chatterjee

University of Cambridge

Disorders of nuclear hormone synthesis and action: genetics and pathophysiology

Professor Chatterjee will explore the role in disease of nuclear hormone receptors, a class of proteins in cells that sense molecules including steroids and thyroid hormones. By studying the genetics of patients with conditions that affect the body’s hormone balance, Professor Chatterjee aims to find unknown causes of gene defects in three conditions: congenital hypothyroidism, resistance to thyroid hormone and peroxisome proliferator activated gamma (PPARγ)-mediated insulin resistance. Success in these studies would lead to better clinical diagnoses and potentially treatment for the disorders.

Professor Alister Craig

Liverpool School of Tropical Medicine

Cytoadherence-mediated pathology in cerebral malaria

Professor Craig will be examining how cytoadherence – the process whereby red blood cells infected with the malaria parasite adhere to the walls of blood vessels – leads to severe cases of malaria. Working with colleagues in Liverpool, Glasgow and at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Professor Craig hopes the knowledge gained will help in the design of new drug treatments for severe malaria, targeted at preventing or reversing the adhesion of the red blood cells to blood vessels in the brain. Around one million people die each year from severe malaria, mainly young children and pregnant women in low-income countries.

Professor Peter Donnelly

University of Oxford

Statistical methods development and analysis of genomic data in health and disease

The use of high-throughput sequencing technologies signals a new era in genetic research, but will present major challenges in data interpretation and analysis. To help harness the potential benefits of this new technology, Professor Donnelly aims to develop new statistical methods and bioinformatics tools to robustly extract information from the large datasets generated. These applications will focus on the genetic basis of human disease and on the transmission of bacterial pathogens and their evolution, naturally and under pressure from vaccines and antibiotics. He will also undertake a series of experimental studies to better understand the process of meiotic recombination in mammals.

Professor Anne Ferguson-Smith

University of Cambridge

Genomic imprinting and the epigenetic control of genome function

Regulation of gene expression is in part controlled by epigenetic modifications that place DNA in its functional chromosome context. Unlike the DNA sequence, these modifications can change in response to the normal environments that cells are exposed to and influence genome function. Professor Ferguson-Smith will apply knowledge of genomic imprinting (an epigenetic process causing genes to be expressed according to which parent they are inherited from) to study the relationship between the DNA and the epigenetic modifications that regulate it. Experiments will explore how the epigenetic code controls gene expression, how epigenetic states are maintained or change during development, and how a developing organism’s normal or abnormal environment affects gene expression, with implications for health and disease.

Dr Pedro Hallal

Federal University of Pelotas, Brazil

A life-course approach for understanding levels, trends, determinants and consequences of physical activity, and to inform interventions and policy for global action

Based in Brazil, Dr Hallal's research focuses on understanding how physical activity is affected by factors throughout the life course, beginning with maternal physical activity during the early phases of fetal development. Chiefly based on a longitudinal study design that follows 16,000 people in four cohorts, the research takes a multidisciplinary approach (based on epidemiology, social science and physiology) to understanding both the determinants of physical activity and its association with chronic disease. Dr Hallal’s strategy also involves coordinating both national and international health policy makers, to promote the uptake of research evidence in the design and evaluation of public health interventions aimed at promoting physical activity and health.

Professor Kenneth Harris

University College London

Integration of internal and external signals in sensory cortex (joint award with Professor Carandini)

Professor Harris's research focuses on the mechanisms by which populations of cells in the brain form information-processing assemblies. In conjunction with Professor Carandini, Professor Harris will employ his award to understand how the brain integrates multiple signals, applying a computational approach to model neuronal signal interactions in the cortex.

Professor David Holden

Imperial College London

Intracellular biology of salmonella and streptococcus

Professor Holden will investigate two important bacterial pathogens of humans: Salmonella and Streptococcus pyogenes. The award will focus on the deployment of novel approaches to dissect the molecular mechanisms that they use to survive and replicate inside host cells.

Professor Dimitri Kullmann

University College London

Synaptic neurology

Professor Kullmann's interests centre on the mechanisms that underlie normal and abnormal excitability of nerve and muscle. Much of his research addresses the basic properties of synapses in the central nervous system, synaptic plasticity, and the biophysical consequences of inherited mutations of ion channels implicated in neurological disease. Professor Kullmann is using his award to address a number of questions about how synapses work, their complement of ion channels, how dysfunction leads to diseases and what this may tell us about treatments, and how interneurons underpin information processing and memory storage.

Dr Mate Lengyel

University of Cambridge

Normative neurophysiology

Dr Lengyel aims to investigate the connections between the biophysical properties of neurons and cognition. He will identify conditions for the optimal operation of neural circuits, and investigate how their various biophysical properties contribute to such near-optimal functioning. These questions will be addressed using cutting-edge theoretical techniques from computational neuroscience, information theory, signal processing and machine learning.

Dr Jan Löwe

MRC-LMB, Cambridge

Molecular architecture of the bacterial actin cytoskeleton

Dr Löwe’s research will focus on understanding the molecular arrangement of filaments in the bacterial cytoskeleton and how these filaments maintain cell shape. To answer these fundamental questions about bacterial cytoskeletal architecture, he will use X-ray crystallography, electron cryomicroscopy, cellular tomography and biochemical techniques.

Professor Stephen O'Rahilly

University of Cambridge

Insulin resistance: lessons from extreme phenotypes

Professor O'Rahilly will use a unique resource established in Cambridge, the Severe Insulin Resistance Cohort, to further explore the genetic contribution in the development of severe insulin resistance. Using a candidate gene approach, along with exome sequencing and cellular investigations, applied to extreme and other phenotypes, the research aims to uncover unrecognised syndromes of insulin resistance and provide insight into mechanisms of disease that might be susceptible to specific therapeutic interventions.

Dr Klaus Okkenhaug

The Babraham Institute, Cambridge

PI3K signalling in immunity and infection

Phosphoinositide 3-kinases (PI3Ks) are enzymes that become activated within cells of the immune system in response to pathogens. As part of this award, Dr Okkenhaug will investigate different forms of PI3K and their roles in immunity and infection.

Professor Laurence Pearl

University of Sussex

Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone system

Professor Pearl will study at a structural level the molecule Hsp90, believed to have a key role in cancer as well as in viral and parasitic infections. In particular, he will be examining whether the molecule is an appropriate drug target for a wide range of diseases.

Professor Fiona Powrie

University of Oxford

Immune pathways in the intestine in health and disease

Our intestines contain a huge number of microbes that play an important part in our health. In inflammatory bowel disease, the beneficial relationship we have with these bacteria breaks down, resulting in chronic and painful intestinal inflammation. Professor Powrie will be investigating how the 'dialogue' between the intestinal immune system and intestinal bacteria breaks down and why this leads to disease.

Professor Sara Rankin

Imperial College London

Pharmacological mobilisation of progenitor cells for tissue regeneration

Professor Rankin is building on previous funding from the Wellcome Trust with the aim of developing innovative ways to activate stem cells to stimulate the regeneration of tissues. In particular, she will investigate the factors that regulate the mobilisation of stem cells from bone marrow as well as characterising these mobilised stem cells. Her research will lead to major advances in our understanding of the biology of stem cells, including the role these cells play in disease pathogenesis, and it will hopefully also lay the foundations for the development of new regenerative medicines.

Professor Wolf Reik

The Babraham Institute, Cambridge

Epigenetic reprogramming in mammalian development

Reprogramming is the erasure and rewriting of epigenetic marks, such as the methylation of DNA and the modification of histones. This phenomenon naturally occurs in germ cells (sperm and eggs) and in the newly formed embryo after fertilisation and is crucial for the establishment of totipotency (the ability of a cell to divide to produce all of the differentiated cells necessary for an organism). Professor Reik will explore the mechanisms of DNA demethylation; the types of epigenetic information that are resistant to erasure, potentially leading to inheritance of epigenetic marks; and how insights from this work can improve approaches in stem cell science and regenerative medicine.

Professor Patrik Rorsman

University of Oxford

Metabolic and hormonal regulation of pancreatic hormone secretion

Professor Rorsman will investigate how islet cells in the human pancreas function in health and disease by understanding the mechanisms that control the secretion of hormones, particularly insulin. Specifically, he plans to show how islet cells respond to the availability of nutrients and examine the crosstalk between the islets and the rest of the body. Professor Rorsman hopes that the knowledge gained will aid in the design of new drug treatments for diabetes.

Professor Peter Rothwell

University of Oxford

Improving prevention of stroke by better understanding of existing risk factors and treatments

A physician and epidemiologist, Professor Rothwell will address the most important – but, he believes, tractable – issues in stroke prevention, including how best to diagnose and treat high blood pressure, how to further reduce the risk of recurrent stroke and how to identify patients at high risk of vascular dementia. He will study patients in two large longitudinal cohorts (Oxford Vascular Study and Oxford Vascular Cognitive Impairment Cohort), using state-of-the-art imaging, biomarker and genetic studies as well as standard clinical investigations to achieve better phenotyping of stroke and hence greater understanding of aetiology and prevention. He will also study how we can increase the benefit of existing treatments, including whether we should use aspirin to prevent cancer as well as heart attacks and strokes.

Professor Christiana Ruhrberg

University College London 

Defining signalling pathways that control neurovascular interactions in the brain and retina

The interaction between nerve cells and cells in our blood vessels controls the development of the brain and retina, regulates traffic across the blood-brain and blood-retina barriers, and promotes the formation of new nerve cells. Professor Ruhrberg will explore the mechanisms that regulate these interactions in normal development, with the aim of identifying therapeutic targets for diseases such as age-related macular degeneration or diabetic retinopathy, in which the nerve cells and blood vessels fail to communicate normally and blood vessels function poorly.

Professor Gavin Screaton

Imperial College London

Studies of immunopathogenesis in dengue virus infection

Professor Screaton will analyse several aspects of the immunology of dengue virus infection, a serious emerging tropical disease. Previous exposure to dengue virus can mean that an individual becomes more unwell when they encounter the virus on a second occasion. To allow better vaccine design and monitoring, there is a need for greater clarity about which components of the immune response are protective and which are damaging to the host.

Professor Christopher Thompson

University of Manchester

Generating order from chaos: understanding how heterogeneity, stochastic differentiation and cell sorting can result in robust developmental patterning

Professor Thompson will be studying a fundamental question in development: cell fate choice and pattern formation. As a model, he will use the social amoeba Dictyostelium. When starved, many thousands of individual amoebae aggregate to form patterned multicellular structures with a small number of different cell types. The patterning mechanism is evolutionarily conserved, but poorly understood as it is based on stochastic differentiation followed by sorting out. Using this model, he will identify and analyse genes that underlie this patterning process and the regulation of altruistic cell death.

Professor Dale Wigley

Imperial College London

Understanding the structure and mechanism of macromolecular machines that regulate chromatin dynamics

Eukaryotic genomes are packed into a highly ordered structure called chromatin, which provides organisation and stability to genetic material. Professor Wigley will study the structure and mechanism of several large protein complexes that interact with nucleosomes to regulate chromatin structure and dynamics in fundamental cellular processes such as transcription, replication and repair.

People we've funded

Many of our grantholders carry out research in Africa and Asia. See our directories: