Grants awarded: Intermediate Clinical Fellowships

2016

Dr Benjamin Fairfax

University of Oxford

Inflammation associated modulation of DNA methylation: an investigation into the genetic determinants and transcriptional consequences

While our immune system protects us against infections, immune responses that continue for too long can actually damage our health. Persistent immune activity can set up a state known as chronic inflammation. Genes involved in regulating inflammation have been associated with many conditions, including Alzheimer’s disease and cancer. DNA methylation is a process in our cells that can turn genes on or off. It is influenced by numerous factors including age, sex, and our genetics. The normal control of methylation is typically lost in cancer.

I am interested in how immune activity alters DNA methylation, how this relates to our genetics, and how it may affect future immunity. I think that past infections may influence future responses by altering our DNA methylation, possibly increasing the risk of inflammation and disease. In this study I will build on findings I have made showing that components of bacteria can alter DNA methylation. I will investigate how other immune stimulants alter DNA methylation and over what timescale. I propose to find out what effects these changes have on turning genes on and off, and whether we can observe them in different diseases, including infections and cancer.

 

 

Dr Golam Khandaker

University of Cambridge

Inflammation and immunity in depression: from novel mechanisms towards therapeutics

It is thought that the immune system can cause depression but the association between depression and systemic inflammation, particularly serum interleukin 6 (IL-6) and other inflammatory mediators, is unclear.

I will apply randomised designs using a healthy population and patients with depression to test conclusively whether the association between IL-6 and depression is causal. Particular attention will be paid to neurovegetative symptoms of depression, such as fatigue, which are likely to be closely related to inflammation. I will apply Mendelian randomisation design to test causality between IL-6 and depression by taking into account genetic determinants of serum IL-6 concentration. For this analysis, 14 cohorts with existing data will be brought together by establishing a consortium to study inflammatory biomarkers in depression. I will also carry out a second study to examine whether neurovegetative symptoms mediate the relationship between IL-6 and depression. A third study will translate experimental findings from animal studies regarding inflammation-induced depression to humans and elucidate whether the IL-6 pathway is causally linked to depression by using a proof-of-concept, double-blind, randomised, placebo-controlled experiment. I will test whether complete inhibition of IL-6 signalling with single intravenous infusion of the drug tocilizumab reduces serum proinflammatory cytokine concentrations and improves neurovegetative symptoms in treatment-resistant depression.

 

 

Dr David McAllister

University of Glasgow

Treatment effectiveness in multimorbidity: combining efficacy estimates from clinical trials with the natural history obtained from large routine healthcare databases to determine net overall treatment benefits

Multimorbidity, where patients have more than one long-term condition, is becoming increasingly common. People with multimorbidity are less likely to receive recommended treatments than people with just one disease, and some clinicians question whether treatment recommendations apply equally to people with multimorbidity. Unfortunately, current approaches to deciding if the benefits of new treatments outweigh the harm are not suited for answering this question. As such, new ways of deciding on the best treatments are needed for patients with multimorbidity.

Two recent developments provide the opportunity to develop an alternative. Data from previous clinical trials are becoming publicly available and we can see how the effect of treatments varies with multimorbidity by combining data from many trials. Also, very large databases are now available which can help us to understand whether or not patients with multimorbidity are able to derive a significant benefit from particular treatments. This study will use modern statistical methods to combine several existing data sources. It will show that new analytic techniques can be used to provide reliable estimates of the balance of benefits and harm for people with multimorbidity.

This work will help to guide future treatment for the increasing number of people with multimorbidity.

 

 

Dr Charlotte Warren-Gash

London School of Hygiene and Tropical Medicine

Role of persisting neurotropic viruses in neurological diseases of ageing

After people have been infected with varicella zoster virus, which causes chicken pox and shingles, or herpes simplex virus, the viruses lie dormant in nerve cells and are there for life. They can reactivate with age or due to poor health, leading to inflammation of nerve cells that can cause chronic pain. Recent research suggests that virus reactivation may also be linked to two other common and debilitating conditions associated with ageing: stroke and dementia. If so, preventing virus reactivation by using vaccines or antiviral drugs may prevent or delay progression of these serious neurological diseases.

This research aims to use a range of data sources that include information on virus reactivation measured by blood antibody levels, health using clinical records, and genes to investigate a series of related questions: whether reactivation of varicella zoster virus is linked to stroke or early stroke, whether reactivation of herpes simplex virus speeds up the onset of dementia or makes it worse, who is most at risk from complications of virus reactivation and when is the best time to intervene.

Answering these research questions will help to target existing interventions better and inform the design of clinical trials of new preventive therapies.

2015

Dr Thomas Bird

University of Edinburgh

The role of Wnt/TWEAK signalling in establishing a zonal hierarchy of liver regeneration

Tom is a hepatologist with an interest in liver failure. He will use his Fellowship to study how the adult liver regenerates and how this is controlled. Using transgenic models to track proliferating cells during liver injury, he will examine why some cells succeed in regenerating while others fail. He will focus on the interactions between the Wnt and TWEAK signalling pathways in specifying regeneration to particular cells within specific areas of the liver. Tom will be based at the University of Edinburgh and the Scottish Liver Transplant Unit but will spend his Fellowship at the CRUK Beatson Institute in Glasgow.

Dr Daniel Davis

University College London

The population impact of delirium on long-term cognitive impairment

Daniel is a geriatrician and epidemiologist interested in delirium and future cognitive impairment. He seeks to track cognitive function before, during and after delirium. Understanding how delirium and/or acute illness contribute to trajectories of cognitive decline will involve recruiting a population sample of older persons, working with existing cohorts in the Dementias Platform UK (UK Biobank, SABRE, Whitehall II, CHARIOT, MRC National Survey for Health and Development) and developing a scalable, informatics-based delirium measure with the Farr Institute @ CIPHER. Daniel will spend part of his Fellowship gaining experience in hospital informatics at the University of California, San Francisco.

Dr Mandy Peffers

University of Liverpool

Defining the role and mechanisms of small nucleolar RNAs in cartilage ageing and disease

Mandy is a veterinary surgeon based at the University of Liverpool with Professor Peter Clegg and Professor George Bou-Gharios. Her research interests include defining the role and mechanisms of small nucleolar RNAs (snoRNAs) in cartilage ageing and disease. Changes in expression of specific snoRNAs may result in a dysregulation of ribosome biogenesis with altered protein translational capacity. This impacts on the chondrocyte phenotype, resulting in a tissue less able to produce the required proteins within it – which contributes to osteoarthritis. Mandy’s work will also be performed under the mentorship of Professor Tim Welting's laboratory in the University of Maastricht and Professor Kylie Vincent at the University of Oxford.

Dr James Ware

Imperial College London

Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification

James is a cardiologist and clinical genomicist. His clinical work focuses on inherited cardiac conditions, and his research aims to understand the genetic basis of cardiovascular disease, and to interpret genomic information so that it can be used in the clinic. James's Fellowship research programme focuses on dilated cardiomyopathy, an inherited heart muscle disease. Together with collaborators in the UK and overseas he is working to identify genes causing severe childhood forms of this disease, and is applying genetics to stratify patients and target therapy.

2014

Dr Sarosh Irani

University of Oxford

The immunobiology of autoantibody-mediated diseases of the central nervous system

Sarosh is a neurologist with a background in the antibody-mediated diseases of the central nervous system – particularly autoimmune encephalitis and autoimmune epilepsies. His Fellowship will explore the cellular immunology of these diseases using flow cytometry, cell culture and proteomic techniques. Sarosh aims to identify pathogenic B-cell populations and understand characteristics which may make them selectively vulnerable to future therapies.

Dr Joanne Jones

University of Cambridge

Autoimmunity after alemtuzumab: a human model to study the role of regulatory T cells in lymphopenia-associated autoimmunity

Joanne is a neurologist with an interest in autoimmunity. By studying individuals with multiple sclerosis (MS) treated with the highly effective and recently licensed lymphocyte-depleting monoclonal antibody alemtuzumab, she aims to understand why autoimmunity often occurs as T cells recover from depletion. MS patients treated with alemtuzumab offer a rare opportunity to study this phenomenon directly in humans, as one in three develop a new (usually thyroid) autoimmune disease following treatment. Joanne’s Fellowship will focus on the role of regulatory T cells in controlling homeostatic responses to T-cell depletion, and lymphopenia-associated autoimmunity.

Dr Veronica Kinsler

University College London

Functional characterisation of the role of PPP2R3B in malignant melanoma

Veronica is a paediatric dermatologist with a particular interest in rare genetic neurocutaneous disorders and mosaicism. Her research into the pathogenesis of these rare conditions sheds light on the genes involved in normal development, and in more common skin conditions. Her Fellowship focuses on a new gene involved in melanoma, and the potential for therapeutic manipulation of the signalling pathways it affects. Veronica is based at the UCL Institute of Child Health and will spend half her Fellowship at the CRUK London Research Institute.

Dr James Lee

University of Cambridge

Long non-coding RNAs in immunity and disease pathogenesis

James is a gastroenterologist with a clinical interest in inflammatory bowel disease (IBD) and a background in genetics, genomics and immunology. During his Fellowship, he will examine the role of previously uncharacterised long non-coding RNAs in the immune system, and, having shown that several of them lie within IBD-associated genetic loci that are devoid of protein-coding genes, investigate how these might contribute to IBD pathogenesis. James will be based at the University of Cambridge and will spend half of his Fellowship at Harvard University.

Dr Eoin McKinney

University of Cambridge

Tired of relapsing: manipulating T-cell exhaustion as a treatment for autoimmune disease

Eoin is a nephrologist with an interest in the pathways driving and marking severe, relapsing autoimmune disease. He is using his Fellowship to explore parallel ways in which the immune response deals with persistent infection and persistent self-antigen during a number of relapsing autoimmune and inflammatory diseases. He is using a cellular model of T-cell differentiation that recreates changes seen in patients with relapsing disease. Using a combination of bioinformatics, virology and cellular immunology techniques, Eoin aims to modify those changes and to identify novel targeted treatment strategies for patients.

Dr Rachel Myles

University of Glasgow

Heterogeneity of sympathetic stimulation as a mechanism of ventricular arrhythmias following myocardial infarction

Rachel is a cardiologist with an interest in the ventricular arrhythmias which cause sudden death in patients who have survived a heart attack. She is based at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, where she works with Professor Godfrey Smith, using state-of-the-art optical imaging techniques to understand arrhythmia mechanisms. During her Fellowship, Rachel will work with collaborators in the UK and the US to examine the role of changes in the autonomic nervous system in triggering and sustaining arrhythmias after a heart attack, with the aim of developing alternative therapies to the implantable defibrillator.

Dr Chi Wong

Wellcome Trust Sanger Institute

Mechanistic role of CUX1 in haematopoiesis and leukaemogenesis

Chi is a haematologist interested in the basis of poor-prognosis myeloid malignancies, particularly those characterised by chromosome 7q loss. He will examine the consequences of loss of a chromosome 7q gene, CUX1, which confers poor clinical outcome when mutated or deleted in myeloid malignancies. Chi will use genome-editing technologies to create genetic models that recapitulate these disorders. By using bioinformatics, cellular and molecular biology techniques, he will decipher how loss of CUX1 and other candidate tumour suppressor genes promotes myeloid malignancy in vivo. In parallel, he aims to identify specific therapies targeting CUX1-mutant tumours through genetic and drug-sensitivity screening technologies.

2013

Dr Kenneth Baillie

University of Edinburgh

Identification and characterisation of host factors underlying susceptibility to influenza

Ken is an intensive care doctor with an interest in genetic susceptibility to flu. He is using his Fellowship to find specific genes in humans that make otherwise healthy people vulnerable to severe, life-threatening flu. He is employing bioinformatics, statistics, and cell biology approaches to identify genes that may be important in this process, and has identified several genes that may be used in the future to design treatments for critically ill flu patients.

Dr Venetia Bigley

Newcastle University

Mapping the genetic and cellular basis of human dendritic cell haematopoiesis

Venetia is a haematologist with specialist clinical interests in bone marrow transplant, adult primary immunodeficiencies and the histiocytoses. Her Fellowship supports her work to better understand the cellular pathways and genetic control of dendritic cell haematopoiesis, the genetic causes of dendritic cell primary immunodeficiencies, and the immunological consequences of dendritic cell deficiency. Venetia is based in the Human Dendritic Cell Laboratory, Newcastle University, and collaborates with Dr Sophie Hambleton, Dr John Dick (University of Toronto/Ontario Cancer Institute) and Professor Florent Ginhoux (Singapore Immunology Network).

Dr David Hunt

University of Edinburgh

Activation of the type 1 interferon response by nucleic acids: a fundamental mechanism causing human neuroinflammatory disease

David is a neurologist with an interest in neuroinflammatory disease. His research aims to understand the mechanisms which initiate and drive neuroinflammation. David works with Professor Andrew Jackson at the Institute of Genetics and Molecular Medicine, Edinburgh, studying how reduced nuclease activity causes the innate immune response to be aberrantly activated in the human brain.

Dr Rickie Patani

UCL

Capturing initial molecular events in the pathogenesis of motor neurone disease

Rickie's research aims to molecularly define the precise roles of RNA metabolism and cellular autonomy in the pathogenesis of motor neurone disease (MND). To robustly investigate initiating molecular events, Rickie will use disease-specific human induced pluripotent stem cells, together with novel functional genomic methodologies (developed in Professor Jernej Ule's lab, UCL), to elucidate post-transcriptional mechanisms of neurodegeneration. This work will begin to resolve the molecular pathogenesis of MND in order to guide a more mechanistically rationalised therapeutic strategy for this rapidly progressing and universally fatal condition.

Dr Nick Powell

King's College London

The role of microRNA-142 in mucosal immunity

Nick is a gastroenterologist interested in the molecular mechanisms that regulate the mucosal immune system, particularly in the context of intestinal inflammation, including inflammatory bowel disease (IBD). His Fellowship will focus on defining the role of a specific microRNA species that appears to be highly expressed by immune cells in the gut. Specifically, he will examine the role of miR-142 in controlling inflammatory and regulatory pathways of innate immune cells in the gut, with the aim of defining novel pathways that may be amenable to therapeutic intervention in IBD.

Dr Alex Shortt

UCL

Investigating the immune response to somatic corneal stem cell allografts

Alex is a surgical ophthalmologist investigating the use of stem cell transplants to treat corneal disease. The response of a recipient's immune system to engrafted stem cells is likely to be an important determinant of transplant success. During his Fellowship, Alex will examine the interaction between tissue-specific stem cells and the immune system, using the eye as a model. The project brings together his experience in corneal stem cell biology and the immunology expertise of his collaborators, Dr Emma Morris and Professor Hans Stauss of the UCL Institute of Immunity and Transplantation.

Dr Karin Straathof

UCL

Anaplastic lymphoma kinase-targeted immunotherapy strategies as treatment for neuroblastoma

Karin is a specialty registrar in paediatric oncology. Her research interest is in the development of T-cell-based immunotherapy strategies for childhood tumours. Using a chimeric antigen receptor, a desired tumour specificity can be grafted onto a patient's own T cells. Karin's Fellowship supports her work in developing this type of engineered T-cell therapy for neuroblastoma. Specifically, her work focuses on the development of a chimeric antigen receptor that recognises an antigen specific to neuroblastoma, and the evaluation of its function in an in vivo model. This information will inform the rapid translation of this immunotherapy strategy into a clinical study.

Dr Emma Thomson

University of Glasgow

T-cell-mediated evolution of the hepatitis C virus during acute infection

Emma is an infectious diseases specialist with an interest in T-cell-mediated evolution of the hepatitis C virus (HCV). During her Fellowship, Emma aims to identify novel epitopes targeted during early HCV infection using next-generation sequencing and functional T-cell assays. This work is designed to advance the search for an effective HCV vaccine.

Dr Laurie Tomlinson

London School of Hygiene and Tropical Medicine

Drug-associated acute kidney injury: who gets it, when and why?

Laurie is a nephrologist with research interests in acute kidney injury and the role that commonly prescribed medications play in its development. She is based at the London School of Hygiene and Tropical Medicine, working with Professor Liam Smeeth. Her Fellowship will support a project using large primary care databases to find optimal ways to define acute kidney injury and to study how the interplay of patient factors, medication use and infections promotes the development of the condition. Understanding these factors will enable development of guidelines for safer prescribing in the growing population of older people with multiple comorbidities.

2012

Dr Michael Chapman

University of Cambridge

The role of aberrant RNA processing in the pathogenesis of multiple myeloma

Dr Matthew Daniels

University of Oxford

Induced pluripotent stem cell models of hereditary cardiomyopathy

Matthew is a cardiologist with clinical interests in inherited cardiac conditions and percutaneous device closure of structural cardiac defects. His Fellowship supports his work to generate in vitro models of inherited heart disease using induced pluripotency. An essential part of this programme is the development of better ways to produce and characterise the biology of living heart cells made in the dish.

Dr Susanna Dunachie

University of Oxford

Identification of T-cell epitopes for vaccine targets against melioidosis in North East Thailand

Susanna is an infectious diseases physician based at the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme in Bangkok. She is studying the immune response to the tropical disease melioidosis in patients admitted to hospital. Her work aims to find targets for vaccination and set up capacity for field immunology in Thailand. Susanna's collaborators include Dr Rosemary Boyton at Imperial College, Dr Helen Fletcher at the London School of Hygiene and Tropical Medicine, and Professor Adrian Hill at the Jenner Institute, University of Oxford. She has also worked with Professor Tom van der Poll and Dr Joost Wiersinga at the Academic Medical Center, Amsterdam.

Dr David Ferenbach

University of Edinburgh

The effect of ageing upon renal injury and repair

David is a nephrologist with research interests in acute kidney injury, focusing on the influence of ageing on renal injury and repair. David is based in the laboratories of Professors Joe Bonventre and Amy Wagers at Harvard Medical School. His goal is to generate novel experimental systems to characterise circulating and cellular factors responsible for the 'aged' kidney phenotype after kidney injury and fibrosis. Understanding such factors could form the basis for new therapies for age-associated disease.

Dr Sonia Gandhi

UCL

The role of alpha-synuclein misfolding in Parkinson's disease

Sonia is interested in the molecular pathogenesis of Parkinson's disease. Her aim is to understand how protein misfolding results in neurotoxicity. To achieve this, novel biophysical techniques of single-molecule FRET will be employed to resolve the molecular behaviour of aggregating alpha-synuclein (with Professor David Klenerman, University of Cambridge). The effect of these different aggregated forms of alpha-synuclein will then be assessed in a range of human stem cell-derived models of Parkinson's disease at the UCL Institute of Neurology, working with Professor Linda Greensmith. This work will help to resolve how alpha-synuclein oligomerisation induces pathophysiology.

Dr Manju Kurian

UCL

Infantile parkinsonism due to dopamine transporter deficiency: functional characterisation and therapeutic approaches

During her Fellowship, Manju is continuing her research in identifying the cause of infantile parkinsonism in a subgroup of patients with mutations in the gene encoding the dopamine transporter (SLC6A3). She plans to further elucidate disease-causing mechanisms in this disorder by producing a dopaminergic cell model from induced pluripotent stem cells, derived from affected patients. This neuronal cell model will be studied for dopaminergic-cell-specific properties that will enable her to further understand the pathophysiology of this newly identified disorder.

Dr Richard Mellanby

University of Edinburgh

Investigation of factors necessary for dendritic cells to initiate autoimmunity

The key goal of Richard's research is to use novel models of dendritic cell (DC)-driven autoimmunity to establish which DC factor(s) are necessary to initiate an autopathogenic T-cell response, re-trigger autopathogenic T cells and render T cells non-pathogenic. He is investigating which TLR ligands enable DCs to drive an autopathogenic T-cell response. He is also using candidate gene and transcriptomic approaches to establish the factors that DCs must provide to initiate autoimmune pathology. It is hoped that a better understanding of this key immunological process will offer insights into how autoimmune diseases can be prevented and potentially cured.

Dr Rod Mitchell

University of Edinburgh

The germ stem cell niche in the human testis and the origins of testicular cancer

Rod is currently investigating the development of germ cells in the testis in relation to future fertility and the origins of testicular cancer. The project aims to identify what defines the germ cell niche in the human fetal testis. It will also determine how alteration of the niche by genetic, environmental or other factors could affect germ cell differentiation, which may result in effects on future fertility or the development of testicular cancer in adulthood. This work is being undertaken in collaboration with Professor Richard Sharpe at the Centre for Reproductive Health and Professor Stuart Forbes at the Centre for Regenerative Medicine.

Dr Serena Nik-Zainal

Sanger Institute

Exploring the biological processes underlying mutational signatures identified in cancers

Somatic mutations in cancer genomes have been generated by multiple DNA damage processes, the effects of which are mitigated by the cellular repertoire of DNA repair pathways. Each process leaves a characteristic imprint, or mutational signature, on the cancer genome. Current biological understanding of these mutational signatures is remarkably limited. Serena aims to explore the biological basis of mutational signatures that emerge from cancer genomes by studying mutational signatures that arise in patients with inherited genetic defects in DNA repair/replication machinery. She will also explore signatures generated through the experimental manipulation of components of the DNA repair/replicative machinery in model systems.

Dr Nadia Schoenmakers

University of Cambridge

Investigation of the genetic basis of congenital hypothyroidism

Nadia aims to identify novel genes involved in thyroid development and hormone biosynthesis in a patient cohort with congenital hypothyroidism, using genetic approaches including whole-exome sequencing. She elucidates their role in thyroid biology with studies in cellular and appropriate model systems. Her research integrates with a wider programme, with the work of Professor Krishna Chatterjee in the Institute of Metabolic Science at the University of Cambridge.

Dr Anthony Solomon

London School of Hygiene and Tropical Medicine

Tools for the elimination of blinding trachoma

Sol is an infectious diseases physician with a research focus on neglected tropical diseases. His Fellowship focuses on trachoma, the most common infectious cause of blindness, which is found where water, sanitation and access to healthcare are in short supply. By refining and applying new methods for determining the ocular bacterial load in individuals and for detecting the presence of infection transmission within populations, he hopes to help inform strategies for global trachoma elimination.

2011

Dr Behdad (Ben) Afzali

King's College London

The relevance of regulatory T-cell conversion to T helper 17 for the balance between tolerance and inflammation

Ben will study the in vivo relevance and mechanisms underlying the conversion of anti-inflammatory human regulatory T cells into pro-inflammatory T helper (Th) 17. Understanding the Treg/Th17 fate decision will provide significant insights into disease mechanisms, inform strategies for treating autoimmune diseases and transplant rejection, and anticipate potential complications of Treg therapy during inflammation. This work will be carried out jointly at King's College London in the laboratory of Professor Sir Robert Lechler and at the National Institutes for Health, USA, in the laboratory of Professor John O'Shea.

Dr Jeremy Day

University of Oxford

Population structure and pathogenicity of C. neoformans in Vietnam

Jeremy is based at the Wellcome Trust Major Overseas Programme, Vietnam, investigating the population structure, ecology and pathogenicity of the saprophytic yeast Cryptococcus neoformans, an important cause of meningitis. He is studying closely related genotypes associated with distinct clinical phenotypes, identifying how they fit into the wider population and their environmental niches. Jeremy is using RNA-seq to define patterns of gene expression that are associated with differing degrees of virulence in infection models. Hypotheses generated from these experiments will be tested in clinical samples; the ultimate goal is the identification of new drug targets. The research will include time spent at Duke University, USA.

Dr Rashida Ferrand

London School of Hygiene and Tropical Medicine

Treatment support for older children and adolescents living with HIV: a household randomised trial linked to evaluation of decentralised HIV testing and care in Harare, Zimbabwe

Rashida is investigating interventions to improve HIV testing and care for older children and adolescents. The effectiveness of primary care-based opt-out HIV testing in reducing the community burden of undiagnosed HIV for this age group will be investigated. A randomised controlled trial of community worker-delivered support intervention to households with HIV-infected children will be conducted, to improve retention into HIV care and adherence. The study will also investigate the impact of HIV treatment on chronic lung disease and growth failure through a cohort study. Rashida is collaborating with the University of Oxford to investigate immunogenetic correlates of slow HIV progression in children.

Dr Dominic Furniss

University of Oxford

Unravelling the molecular genetics of Dupuytren's disease

Dominic is a plastic surgeon whose research focuses on the molecular genetics of Dupuytren's disease. Dupuytren's disease is the most common inherited disease of connective tissue and affects around 4 per cent of the UK population. It is a fibroproliferative disease characterised by collagenous palmar nodules and cords, which cause the fingers to flex into the palm, leading to severe functional problems. Dupuytren's disease is an archetypal complex disease, and Dominic's group are undertaking a large genome-wide association study to elucidate the underlying genetic predisposition, with the aim of developing novel therapies.

Dr David Kavanagh

Newcastle University

The convergence of complement and coagulation in atypical haemolytic uraemic syndrome

David is a clinical academic nephrologist at Newcastle University. His laboratory focuses on complement-mediated renal disease. During his Fellowship he will focus on atypical haemolytic uraemic syndrome, the archetypal disease of complement over-activation, which results in end-stage kidney disease owing to the formation of platelet fibrin thrombi in the glomerulus. He will use this model disease to investigate the complement/coagulation axis.

Dr Tim Kendall

University of Edinburgh

The role of mesothelial cells and the p75NTR/sortilin axis in hepatic injury, fibrosis and regeneration

Tim is exploring the expression of Wt1 in liver fibrosis and regeneration, with a particular focus on its role in hepatic stellate cell activation. He is also determining the role of the sortilin-proneurotrophin axis in hepatic stellate cell survival. The work at the University of Edinburgh is being undertaken with Professor Nick Hastie at the MRC Human Genetics Unit, Professor John Iredale in the MRC Centre for Inflammation Research, and Professor Stuart Forbes at the MRC Centre for Regenerative Medicine.

Dr Frank McCaughan

University of Cambridge

SOX2 and squamous lung cancer

Frank is developing novel genetically switchable model systems of bronchial dysplasia and squamous lung cancer that will recapitulate the human disease. The work is being performed with Professor Gerard Evan at the Department of Biochemistry, University of Cambridge, and in collaboration with clinical colleagues at King's College, London.

Dr Kiran Nistala

UCL

Regulatory and effector B-cell function in childhood rheumatic disease

Kiran is a paediatric rheumatologist working on the molecular control of regulatory B-cell function in the laboratory of Professor Claudia Mauri. Using gene expression arrays, he has identified several candidate genes that regulate IL-10, a key immunoregulatory cytokine produced by B cells, and will be testing their role using a model system. He aims to translate these findings to the context of rheumatic disease by working at Great Ormond Street Hospital, together with Professor Lucy Wedderburn, to study a rare childhood form of inflammatory myositis called juvenile dermatomyositis.

Dr Elspeth Payne

UCL

Identifying novel therapeutics and disease mechanisms for ribosomal protein-mediated human haematopoietic diseases

Beth is a haematologist with an interest in bone marrow failure and myelodysplastic syndromes. Her Fellowship focuses on understanding the contribution of aberrant protein translation in haematopoietic cells of patients with ribosomal protein disorders and identifying novel therapeutics through in vivo chemical screens using the zebrafish model.

Dr Neil Rajan

Newcastle University

Integrative genomic profiling of inherited cutaneous tumours

Neil's major research theme is to use inherited cutaneous tumour syndromes to explore fundamental cell-signalling pathways in the skin. Using patient-derived samples from families who are susceptible to multiple skin tumours, his project aims to discover novel druggable targets that may be relevant to both rare disease and common skin tumours. His work will be undertaken at Newcastle University and at the Institute for Cancer Research under the supervision of Professor Alan Ashworth.

Dr Ben Seymour

University of Cambridge

Mechanisms of endogenous analgesia

Ben studies how the human brain processes pain. His research involves neurophysiological and neuroimaging experiments that probe how we perceive and respond to pain, and he uses the results to build computational models of the underlying neural mechanisms. Ultimately, he aims to use these insights to design new technology-based treatments for pain patients. He works at the Computational and Biological Learning Lab, University of Cambridge, and is supervised by Professor Daniel Wolpert and Professor Trevor Robbins. Part of Ben's Fellowship is based in Japan, where he studies new methods in theoretical neuroscience and neural engineering.

Dr Shishir Shetty

University of Birmingham

CLEVER-1 mediates the transmigration of regulatory T cells across hepatic sinusoidal endothelium and promotes resolution of chronic hepatitis

Shishir's research focuses on the role of the scavenger receptor CLEVER-1, expressed on liver endothelial cells, in immune cell trafficking to the liver. Using liver injury models that mimic liver disease in humans, he will study the role of CLEVER-1 in the development of hepatitis and progression to liver fibrosis. His aim is to identify potential organ-specific therapeutic targets for chronic inflammatory liver disease. This work will be carried out at the Centre for Liver Research at the University of Birmingham and in collaboration with Professor Sirpa Jalkanen at Turku University, Finland.

Dr George Tofaris

University of Oxford

Studies on alpha-synuclein degradation and its relevance to Lewy body disease

George is using his Fellowship to establish his laboratory at the University of Oxford. He aims to study mechanisms of lysosomal degradation and their relevance to Parkinson's disease. He is also investigating whether key enzymes in these pathways could be targets for neuroprotective therapies.

2010

Dr Francesca Barone

University of Birmingham

The role of leukocyte-stromal cell interactions in the pathogenesis of salivary gland inflammation and Sjogren's Syndrome

Dr Robert Gray

University of Edinburgh

Calprotectin is released in neutrophil extracellular traps in response to infection and is central to CF lung inflammation

Dr Ravindra Gupta

UCL

Characterisation of host-pathogen interections involving mucosally transmitted HIV 1 founder viruses

Ravi's work focuses on three areas. (i) HIV host pathogen interactions and relevance to HIV 'cure' efforts. His group is investigating the details of macrophage infection by clinical isolates. Macrophages are a crucial component of the immune system and a unique cell type in terms of access to sanctuary sites, thus representing a difficult-to-treat reservoir. (ii) Exploring the viral determinants of successful transmission by examining HIV genes individually from both acute and chronic infection. (iii) In vitro HIV drug resistance to protease inhibitors and implications for global scale up of antiretroviral therapy.

Dr Neil Harrison

University of Sussex

Mechanisms of human sickness

Neil will study how systemic inflammation impacts the brain, resulting in changes in mood, memory and cognition. His research aims to offer new insights into the role of inflammation in fatigue and common mental illnesses such as depression. He will start his Fellowship in the laboratory of Professor Hugo Critchley at Brighton and Sussex Medical School, University of Sussex. The latter part of his project will be carried out in Professor Carmine Pariante's laboratory at the Institute of Psychiatry, King's College London.

Dr Nicholas Juleff

The Pirbright Institute

Understanding foot-and-mouth disease virus persistence in African buffalo

Foot-and-mouth disease virus (FMDV) infects numerous cloven-hoofed livestock and wildlife species and is a constant threat to the global livestock industry. Buffalo act as maintenance hosts for FMDV in southern Africa, contributing to an epidemiological situation that presents an impasse to rural development and conservation. It is not clear how FMDV is maintained in buffalo or transmitted from carrier buffalo. Nick is currently investigating the mechanisms of FMDV maintenance within individual buffalo and at the population level. Nick will undertake his work at the Pirbright Institute, Kruger National Park and Onderstepoort Veterinary Institute, in collaboration with the University of Glasgow and University of Edinburgh.

Dr Andrew Prendergast

Queen Mary University of London

The impact of microbial translocation and immune activation on the health of Zimbabwean children

Andy is investigating the role of enteropathy in the pathogenesis of malnutrition and HIV infection in Africa. He is based at the Zvitambo Project in Harare, Zimbabwe, where he is undertaking a cluster-randomised trial exploring the impact of improved sanitation and hygiene and/or improved nutrition on stunting and anaemia in infants. The aim of the laboratory work that will underpin this public health trial is to understand the overlapping and interacting causes of enteropathy in this setting, and their relative contributions to child health outcomes in low-income countries.

Dr Rhys Roberts

University of Cambridge

The Charcot-Marie Tooth diseases and associated defects in membrane transport

Rhys is based at the Cambridge Institute for Medical Research, investigating the inherited peripheral neuropathy Charcot-Marie-Tooth disease. He is focusing on the demyelinating forms of the disease, in which many of the patient-associated mutated genes encode proteins known to have important roles in intracellular membrane transport. Rhys's overall goal is to understand the molecular mechanisms that underlie peripheral nerve myelination by Schwann cells and the processes that become dysfunctional when disease-associated genes are mutated.

Dr Argyris Stringaris

King's College London

The developmental psychopathology of irritable mood and its links to depression: genetic and environmental risks, neuropsychological mechanisms, and hormonal influences

Argyris is collaborating with Professor Adrian Angold from Duke University in the USA and Professor Barbara Maughan at the Institute of Psychiatry in London to study the developmental trajectories of irritable and depressed mood, investigating the role of pubertal stage and sex hormones. Together with Dr Louise Arseneault and Professor Terrie Moffitt, he will be furthering his work on the genetics of depression and identifying environmental influences on inter-individual variation of dysphoric mood. Argyris is also collaborating with Professor Andrew Pickles at the Institute of Psychiatry, developing statistical approaches to longitudinal data that could bring him closer to identifying causal mechanisms.

Dr Romain Volmer

University of Cambridge

Activation of the endoplasmic reticulum stress sensor IRE1 by lipid perturbations during flavivirus infections

Romain is working with Professor David Ron at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge studying lipid-induced endoplasmic reticulum stress. His aim is to understand the mechanisms by which lipid perturbations trigger endoplasmic reticulum stress and to analyse whether lipid perturbations contribute to the activation of the endoplasmic reticulum stress pathways during infections by flaviviruses.

Dr Valerie Voon

University of Cambridge

Dissecting compulsivity

Valerie is a neuropsychiatrist interested in the relationship between disorders of natural and drug rewards, or behavioural and substance addictions. Her group focuses on cognitive mechanisms such as impulsivity, compulsivity and motivation using behavioural, physiological and pharmacological challenges and structural and functional imaging modalities, in both clinical populations and healthy volunteers.

2008-09

2008

Dr Sara Brown

University of Dundee

Factors modulating the effects of filaggrin haploinsufficiency in ichthyosis vulgaris and atopic eczema

Sara is a clinical academic dermatologist. Her main research interest is the identification of genetic mechanisms in atopic eczema. She began her Fellowship working with Professor Alan Irvine in Dublin at a tertiary referral centre for paediatric eczema. She is now working in Professor Irwin McLean's laboratory in Dundee, a centre of excellence in eczema genetics and the filaggrin gene. Sara's current work includes eczema transcriptome analysis, collaborative genome-wide association studies of eczema and related phenotypes, and the application of next-generation sequencing for whole-exome analysis of eczema cases.

2009

Dr Tihana Bicanic

St George's, University of London

The impact of C. neoformans phenotype and genotype on the clinical course and outcome of human cryptococcal meningitis

Tihana is working on the pathogenesis of cryptococcal meningitis, an AIDS-defining opportunistic infection caused by the fungus Cryptococcus neoformans. Using a large bank of clinical isolates from clinical trials in Africa, she has been examining the contribution of C. neoformans diversity to clinical presentation in human cryptococcosis. Specifically, she has analysed the role of the cryptococcal capsule – an important virulence factor – in the development of raised intracranial pressure, a common complication of cryptococcal meningitis. In addition, she has explored the effect of other cryptococcal virulence factors (melanisation and macrophage uptake), as well as genotype of the infecting strain, on the outcome of infection.

Dr Mark Dawson

University of Cambridge

Chromatin regulation of self-renewal transcriptional programmes in leukaemia stem cells

Mark has spent his Fellowship helping to establish a novel therapeutic paradigm for the treatment of aggressive haematological malignancies. His work, published in 'Nature' in 2011, demonstrated that targeting chromatin/epigenetic readers could provide excellent efficacy in acute myeloid leukaemia. This study, with others, has provided the platform for phase I clinical trials with this new class of compounds. In addition, Mark has authored three book chapters and nine other manuscripts and has been invited to speak at several national and international conferences on cancer epigenetics. These opportunities have strengthened his long-term ambition to be a leading researcher in this field.

Dr Bruna Galobardes

University of Bristol

Life course inequalities in asthma: estimating its burden and understanding its aetiology

Bruna's research aims to describe and quantify the magnitude of inequalities in asthma and related disease phenotypes throughout the life course and to identify the mechanisms that underlie these inequalities. To this end, her project uses data from some of the leading birth and adult cohorts, in terms of detailed asthma phenotypes and indicators of socioeconomic conditions. Understanding the exposures that mediate inequalities in asthma will make it possible to tackle the inequitable burden of this condition on subgroups of the population but, importantly, it will also provide the means of reducing the overall burden of disease and advancing knowledge on relevant aetiological factors.

Dr Muzlifah Haniffa

Newcastle University

Ontogeny and function of human dermal dendritic cells

Muzlifah is based in the Human Dendritic Cell Laboratory, Newcastle University, with Professor Matthew Collin. Her research aims to understand the functional diversity of human dendritic cells and exploit their immunological properties for therapy. In addition, she aims to provide a framework to align human and murine dendritic cell networks using a comparative immunobiology approach. Muzlifah collaborates closely with Dr Florent Ginhoux in the Singapore Immunology Network.

Professor Emily Holmes

University of Oxford

A psychological approach to understanding and treating bipolar disorder: investigating new cognitive mechanisms

Dr Rachel Lennon

University of Manchester

Are interactions between glomerular podocytes and extracellular matrix compromised in proteinuric kidney disease?

Cell adhesion in the glomerulus is essential for normal barrier function, and Rachel's research team is focusing on the kidney cell-extracellular matrix interface and the unique podocyte cell-cell junction as targets for intervention. She is based in the Wellcome Trust Centre for Cell-Matrix Research and is combining mass spectrometry-based proteomics, systems-level analyses and ultrastructural imaging to investigate the glomerular extracellular matrix and thereby generate new hypotheses about podocyte regulation during development and disease. This approach is now being translated to investigations of podocyte junctions and will be applied to investigate microenvironmental regulation and dysregulation in disease.

Dr Henry Mwandumba

University of Liverpool

Defects in alveolar macrophage innate immune function and increased susceptibility to pulmonary infections in HIV-infected adults

Henry is an infectious disease physician investigating changes in innate immune responses in the lung and how they may increase the risk of lower respiratory tract infections in HIV-infected adults. His research focuses on understanding how HIV, alone or in combination with respiratory co-infections, affects the innate physiological functions of alveolar macrophages (the cells largely responsible for pulmonary innate immunity). Henry believes that a better mechanistic understanding of how HIV alters pulmonary immunity could lead to the development of new interventions to reduce the high incidence of lower respiratory tract infections in HIV-infected individuals.

Dr John-Paul Taylor

Newcastle University

Investigating attentional function and cognitive fluctuations in Lewy body disease: a functional magnetic imaging and electrophysiological study

John-Paul is investigating the neurobiological basis of attentional dysfunction and fluctuations in cognition in Lewy body dementia using a combination of clinical, functional neuroimaging and electrophysiological approaches. John-Paul's work is being performed at the Institute for Ageing and Health, Newcastle University, under the mentorship of by Professor John O'Brien.