Clinical Research Career Development Fellowships: people we've funded
Dr Andrew Conway Morris
University of Cambridge
Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia
Secondary bacterial pneumonia after influenza is a significant, worldwide health problem. Secondary infections were responsible for many deaths in the pandemics of 1918 and 2009. These infections also occur with seasonal influenza and with other respiratory viruses. It is striking that the bacteria that cause these infections commonly live harmlessly in patients’ throats beforehand, and it is unclear how this changes to cause disease.
In previous work I have identified several ways by which systemic inflammation can impair white blood cell function. The aim of this project is to evaluate whether these also facilitate secondary pneumonia and allow colonising bacteria to cause disease. The goals are to determine whether blocking a key signalling molecule (PI3K delta) can prevent development of secondary pneumonia, and to explore the mechanisms by which influenza can impair white blood cells, looking at numbers and function of specific cell types. I will also set up a more life-like model of secondary infection arising from colonising bacteria and explore the changes in the microbes found in the lung (‘lung microbiome’) during infection, and how these may relate to secondary pneumonia.
The ultimate aim is to develop novel, non-antibiotic strategies for preventing and treating secondary pneumonia.
Dr Mariya Moosajee
Institute of Ophthalmology, University College London
Unravelling the molecular complexity behind ocular maldevelopment
Eye birth defects, known as ocular maldevelopment, including abnormally small eyes, clefts of the eye and complete absence of any eyes, occur within the first 4-9 weeks of pregnancy. They cause over a third of the cases of blindness in children worldwide, resulting in profound life-long problems for both the patient and their family. Only a few genes have been found to cause ocular maldevelopment, the majority remain undiscovered and currently there is no treatment available.
The goals of this study are to determine the genetic causes of ocular maldevelopment while carefully detailing the disease characteristics over time to see if any specialist care is needed to minimise associated health problems. Another aim is to identify chemical changes, called methylation, in our DNA that influence genes being switched on or off at crucial points during normal eye development, to form a reference guide for comparison with patients. Using this information, a 3D model of the developing eye will be made from stem cells derived from patient’s skin to investigate changes in genes that cause ocular maldevelopment. This will allow us to develop new therapies.
Once we understand the genetic causes, a real focus on treatments can be made. This study will allow accurate diagnosis and genetic counselling and improved care pathways for patients and families.
Dr Eleanor Raffan
University of Cambridge
Obesity: exploiting genomes for novel insights
When so many people share sedentary lifestyles and ready access to junk food, why do only some become fat? Evidence shows that 40-70% of the difference is down to genes, but only a fraction of those responsible are known. I study pet dogs to find links between genes and obesity. Dogs are commonly obese, share genes and lifestyles with humans and selective breeding means they have unusual genetics which can be helpful when trying to identify obesity genes. Labradors are prone to obesity and they are notoriously obsessed with food. I recently showed that a quarter of Labradors have a genetic mutation, known as POMC, which breaks a brain mechanism that usually switches off hunger.
I intend to study Labradors to learn about how the affected gene controls the body’s energy balance. The affected part of POMC is important in people but different in rodents so it has been difficult to study before. I will also test several other breeds of dog to find new obesity genes. Early results show that my approach works and the genetic areas identified are important in humans too.
Comparing dogs and humans will identify genes influencing obesity in both which can be targeted for future study with the aim of understanding the biology obesity and how to treat it.
Dr Carlo Rinaldi
University of Oxford
The role of BMP signalling in diseases of the motor unit
Spinal and bulbar muscular atrophy (SBMA) is a genetically transmitted neuromuscular disease characterised by muscle weakness and atrophy secondary to dysfunction and death of motor neurons. Recent evidence about SBMA and other neuromuscular diseases has shown that skeletal muscle also plays a critical role in the disease and strongly influences motor neuron survival. These observations hold great potential for therapeutic pathways, particularly because muscle is much more accessible than motor neurons for pharmacological intervention.
The focus of my research is to understand the mechanisms causing the muscle atrophy in SBMA and how muscle signals back to motor neurons to affect their function. In this study I will investigate the role of the bone morphogenic protein (BMP) pathway in SBMA. The reasons why I chose to study this pathway are because the BMP pathway has been recently found to be the most important regulator of muscle mass and BMPs are known to act as muscle-secreted retrograde signals to motor neurons. Preliminary data have shown that this pathway is severely dysregulated in SBMA.
This work has the potential to pave the way to develop a new therapeutic strategy for SBMA and other neuromuscular diseases.
Dr Anna Seale
London School of Hygiene and Tropical Medicine
Which maternal infections are associated with stillbirths and early neonatal deaths in East Africa?
Reducing stillbirths and deaths of babies shortly after birth is an international public health priority. Many of these deaths are caused by infections passed on from the mother. Identifying the infections is important for devising vaccination or treatment, but there is not much data on this.
I propose to describe which maternal infections contribute to the deaths of babies in Kilifi, Kenya, and Harar, Ethiopia, where child mortality is very high and three times that of Kilifi. I will begin by investigating mothers who had their baby at Kilifi County Hospital, Kenya from 2011-16. I will include 350 mothers with stillbirths or babies who died shortly after birth and 350 women who had a healthy baby. I will test stored maternal blood samples for infection and compare the two groups. Then, in a prospective study in Hiwot Fana Hospital, Harar, I will recruit similar numbers of mothers at delivery and test for infection using traditional and new laboratory methods.
This study is based at a new site for the Child Health and Mortality Prevention Surveillance (CHAMPS) network. As this network widens it will be possible to use the results to design studies investigating births outside hospital as well as preventive public health measures.
Dr Andrew Swift
University of Sheffield
Stratification and phenotyping of pulmonary vascular disease with imaging
Pulmonary hypertension (PH) is when a person has high blood pressure in their pulmonary arteries. They patients are short of breath, fatigued and have poor life expectancy. Even in the pure form, called idiopathic pulmonary arterial hypertension (IPAH), there can be big differences in the disease from patient to patient. There is a big challenge to better understand the different types of disease, particularly IPAH and lung diseases, in terms of genetics, response to treatment and life expectancy.
I aim to develop a better way to diagnose patients using computer-based methods to combine information from magnetic resonance images (MRI), together with computed tomography (CT scans). I will also identify patients with common clinical and scan features (called phenotypes) and predict life expectancy. Working with the national IPAH cohort, I will perform a detailed analysis of CT and MRI scans comparing genetic mutations. In addition, working with researchers in the USA on a group of patients with chronic obstructive pulmonary disease (COPD), I will use patient images alongside genetic data to investigate which patients are prone to developing PH, how PH is related to lung disease in COPD and the effect on life expectancy.
Dr Lance Turtle
University of Liverpool
Understanding cross-reactive immunity to Japanese encephalitis virus
Japanese encephalitis (JE) virus is transmitted by mosquitoes and causes brain swelling mostly in children in Asia. It is a member of a family of viruses that includes yellow fever, dengue and Zika. The body responds to viruses by making antibodies. For this family of viruses, antibodies against one virus can cross-react with another virus, because they are all similar. Surprisingly, this cross-reaction can make a second infection worse. This is a particular problem with dengue. However, the cross-reaction can also be helpful. Studying cross-reactions where these viruses naturally occur is difficult, because you cannot tell which virus was first.
This study has a new way of getting round this problem. I will give a live JE vaccine to people in the UK. The body makes antibodies to a live vaccine in the same way it does for a real infection. I will then test the antibodies of the participants who I will split into two groups: people who have never been exposed to these viruses and those who have been vaccinated against yellow fever.
The aim is to identify helpful cross-reactions and minimise the harmful cross-reaction.
Dr Rimona Weil
Institute of Cognitive Neuroscience, University College London
Using visual dysfunction to understand dementia in Parkinson’s disease
Although Parkinson’s is a disease affecting movement, it can also cause problems with thinking and memory. Parkinson’s affects people in different ways, making it difficult to predict what will happen to each patient. If there was a reliable way of telling who will develop dementia, we could work out who would benefit most from early treatments to prevent it. I have developed a sensitive visual test for people with Parkinson’s that can detect whether the ‘thinking’ parts of the brain are involved even before the memory is affected. This test may predict who will get dementia. I have also developed a website where people can sign up to take part in the study.
The aim of this project is to use visual tests combined with brain scanning techniques to understand how dementia develops in Parkinson’s. I want to find out whether this visual test can pick out who will develop dementia before they show any memory problems, what are the changes in structure and wiring in the brains of patients that do not perform as well in the vision test and whether vision tests explain why some patients have distressing hallucinations.