Investigator Award recipients
Investigator Awards provide funding for scientists who have an excellent track record and are in an established academic post. They offer the flexibility and time to enable them to tackle the most important questions in their field. Below are details of recently funded Investigators and the areas they are working in.
July 2013
Detailed information for the July 2013 Investigator Award recipients will be available in the coming months.
New Investigator Awards
Dr Peter Magill, University of Oxford
Neuronal substrates and functional importance of population dichotomy in the external globus pallidus
Senior Investigator Awards
Professor Mohan Balasubramanian, University of Warwick
Using a permeabilized cell system and cell physiology to understand cytokinetic actomyosin ring constriction
Professor Michael Ferguson, University of Dundee
Protein glycosylation in trypanosomes: defining and exploiting a biological system
Professor Frederic Geissmann, King’s College London
AMADEUS
Professor Neil Gow, University of Aberdeen
Making and breaking the cell walls of fungal pathogens
Professor Erhard Hohenester, Imperial College London
Molecular mechanisms of laminin function in health and disease
Professor Vassilis Koronakis, University of Cambridge
Towards a high definition view of cytoskeleton remodelling by the bacterial pathogen Salmonella
Professor Gilean McVean, University of Oxford
The genetic analysis of populations
Professor Markus Müschen, Institute of Cancer Research
Negative feedback and oncogene signalling in leukaemia
Professor Mala Maini, University College London
Immunopathogenesis and immunotherapy of viral hepatitis
Professor Richard Randall, University of St Andrews
and
Professor Steve Goodbourn, St George’s, University of London
The interaction of paramyxoviruses with the interferon system
Dr Jonathan Roiser, University College London
Neural and cognitive processes in depression
Professor Colin Taylor, University of Cambridge
Spatial dynamics of receptor-regulated calcium signalling
Professor Anton van der Merwe, University of Oxford
Immune recognition by non-catalytic tyrosine phosphorylated receptors
Professor Cesar Victora, Federal University of Pelotas, Brazil
Global observatory of trends and inequalities in child health and nutrition
Professor Waldemar Vollmer, University of Newcastle
Bacterial cell wall synthesis and degradation
April 2013
Detailed information for the April 2013 Investigator Award recipients will be available shortly.
New Investigator Awards
Dr Jake Baum, Imperial College London
The cellular and molecular mechanics of malaria parasite invasion of the human erythrocyte
Dr Lindsay Hall, University of East Anglia
Role of early life gut microbiota in colonisation resistance development
Dr Matthew Higgins, University of Oxford
Structural studies of host-parasite interactions at the heart of malaria pathogenicity
Dr Jack Mellor, University of Bristol
The role of acetylcholine in hippocampal function
Dr Nicholas Morton, University of Edinburgh
Discovery and therapeutic development of ‘lean genes’: characterisation of a novel gain-of-function adipose tissue lean gene, thiosulfate sulfur transferase
Dr Jan Rehwinkel, University of Oxford
Cytosolic DNA sensing in infection and autoimmunity
Dr Jessica Strid, Imperial College London
Lymphoid stress-surveillance - linking tumour immune-surveillance and atopy
Dr S Wigneshweraraj, Imperial College London
Non-bacterial regulators of bacterial transcription
Senior Investigator Awards
Professor Luis Aragon, Imperial College London
Functional dissection of mitotic chromatin
Professor Jorge Ferrer, Imperial College London
Understanding regulatory variation in human diabetes
Professor Matthew Freeman, University of Oxford
The control of signalling by members of the rhomboid-like superfamily
Professor Sir John Gurdon, University of Cambridge
Mechanisms for the reprogramming of somatic cell nuclei by eggs and oocytes
Dr Frederick Livesey, University of Cambridge
Human stem cell models of Alzheimer's disease
Dr Andrew McKenzie, MRC Laboratory of Molecular Biology, Cambridge
Innate lymphoid cells in immunity and disease
Professor Jeffrey Pollard, University of Edinburgh
The metastatic cascade: macrophages lead the way
Professor Barry Potter, University of Bath
Chemical biology of cellular signalling using polyphosphate messengers
Professor Matthew Rushworth, University of Oxford
Neural mechanisms for foraging in an uncertain environment
Dr Brigitta Stockinger, MRC National Institute for Medical Research
Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses
Professor John Wood, University College London
Peripheral pain pathways
2012
November 2012
New Investigators
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.
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.
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.
Senior Investigators
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.
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.
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.
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 (e.g. 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 2012
New Investigators
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.
Dr Benjamin Willcox, University of Birmingham
The molecular basis of gamma delta T cell recognition in health and disease
Senior Investigators
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.
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.
May 2012
New Investigators
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 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
Senior Investigators
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 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.
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.
Joint Investigators
Dr James Briscoe, Division of Developmental Biology, MRC National Institute for Medical Research
and
Dr Karen Page, Department of Mathematics, UCL
Regulatory dynamics of vertebrate neural tube development
This joint Investigator Award will draw on the complementary expertise of Drs Briscoe and 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 Elizabeth Fisher, Department of Neurodegenerative Disease, UCL, and
Dr Victor Tybulewicz, Department of Immune Cell Biology, MRC National Institute for Medical Research
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.
Professor Joachim Gross and
Professor 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.
Professor Andrew Hattersley and Professor 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.
February 2012
New Investigator
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.
Senior Investigators
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.
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 2011
New Investigators
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.
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.
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.
Senior Investigators
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.
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.
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 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.
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.
Joint Investigators
Professor William Cookson and
Professor 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.
May 2011
New Investigators
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.
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.
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 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 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 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.
Senior Investigators
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 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 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.
Professor Adrian Hill, Jenner Institute, University of Oxford
T-cell-inducing vaccines
Professor Hill will look at new T-cell-inducing vaccines across a range of infectious diseases assessing new adjuvant strategies to enhance substantially the cellular immune responses elicited. While many existing vaccines target the stimulation of protective antibodies, this study explores the premise that protection by these next-generation vaccines can be improved by increasing the frequency of specific T cells that are induced by vaccination.
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 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.
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 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 Dale Wigley, The Institute of Cancer Research
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.
Joint Investigators
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 Kenneth Harris, Imperial 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.
