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.
Dr Mark Isalan, Imperial College London
Gene network engineering: quantifying emergent gene expression in cancer and antibiotic resistance
Dr Isalan aims to understand and build gene networks that behave predictably, consistently and robustly in the context of solving medically relevant problems. Specifically, his research will explore the emergence of gene expression in response to need in the context of antibiotic-resistance genes in bacteria and multidrug-resistance genes in cancer cells. The main concept at the centre of his research is that natural selection occurs not only at the level of the gene (on genetic variation), but also at the level of gene expression, influencing heritable phenotypic variation. By combining laboratory experiments and computational modelling, he aims to develop a new theoretical basis for understanding emergent gene expression.
Dr George Kassiotis, MRC National Institute for Medical Research
Mechanisms of endogenous retrovirus activation by microbial exposure
Co-infections can compromise key aspects of the immune control of endogenous retroviruses (ERVs). Dr Kassiotis will take a broad but coherent approach to the question of how ERVs are regulated by the immune system and microbial infection. His overall aim is to understand the regulation of ERV expression and its interplay with gut microflora, using a combination of approaches that include mouse models and surveys of human samples. Results could lead to important discoveries that will transform our understanding of ERVs and human disease.
Dr Claudia Kemper, King's College London
Complement receptor signalling in Th-1 immunity
Complement is critically important in human health and disease. Dr Kemper's research seeks to define the function of complement in the regulation of adaptive Th1-mediated inflammation and autoimmune diseases, such as rheumatoid arthritis and scleroderma. She will investigate how the autocrine-activated receptor-signalling network regulates Th1 immunity, how dysregulation of these pathways contributes to Th1-driven autoimmune diseases, and how druggable targets in these pathways can be exploited to have a therapeutic impact upon autoimmunity.
Dr Kevin Maloy, University of Oxford
Regulation of intestinal immune homeostasis by NOD-like receptors
Dr Elizabeth Murchison, University of Cambridge
Genome diversity and evolution in transmissible cancers in dogs and Tasmanian devils
Tasmanian devil facial tumour disease (DFTD) and canine transmissible venereal tumour (CTVT) are the only known examples of naturally occurring clonally transmissible cancers. They are clonal cell lineages that have survived beyond the deaths of the individual hosts that spawned them by acquiring adaptations for the transfer of living cancer cells between hosts. Dr Murchison will catalogue genetic and phenotypic diversity in hundreds of DFTD and CTVT tumours found in geographically dispersed locations. She will use genetic data to explore how these two infectious diseases first arose and subsequently spread through their host populations, and she will investigate how tumour phenotypic diversity may be influenced by genetic and environmental change. She will analyse patterns of selection operating on the two lineages in order to understand factors that have influenced transmissible cancer evolution. In addition, she will investigate the frequency of horizontal DNA transfer in clonally transmissible cancers.
Dr Simon Newstead, University of Oxford
Mammalian peptide transporters as targets for advanced drug design and delivery
Dr Newstead will be investigating at the molecular level the structure and function of the mammalian proton-coupled peptide transporters PepT1 and PepT2, which are important for the uptake of dietary protein and provide a major route for the absorption of drugs. Currently, there is no clear molecular understanding of how PepT1 or PepT2 recognise and transport peptides or drug molecules. The binding sites of PepT1 and PepT2 have to accommodate peptides that vary significantly in size, charge and hydrophobicity, which means that they can also transport chemically diverse drug molecules. The results of Dr Newstead's work should enable the rational design of drugs with improved oral bioavailabilty, through insights gained from the use of sophisticated structural, biochemical and functional studies.
Professor Ewan Pearson, University of Dundee
Stratified medicine in type 2 diabetes: insights from the study of drug response
Type 2 diabetes is a major chronic disease that presents a considerable burden to patients and healthcare systems globally. There has been some progress made on understanding the causes of the disease, particularly in unravelling its genetic aetiology, with this knowledge being applied in clinical practice in monogenic diabetes. The field of stratified medicine in diabetes is currently limited to relatively rare forms of monogenic diabetes. Professor Pearson aims to identify new ways to stratify the disease by developing an understanding (clinical, biochemical and genomic) of why some drugs work well in some people with type 2 diabetes but not others. He will also investigate the mechanisms for variation that explain why some patients respond to diabetes drugs and others experience adverse reactions.
Dr Christopher Petkov, Newcastle University
Neuronal mechanisms for extracting communication signals and signalling sequences: from animal models to humans
There is a great need for better treatments for language disorders and more accurate prognosis of language recovery following stroke. To achieve this, an understanding of the cognitive abilities underpinning language and the critical neuronal circuits and pathways involved is required. Dr Petkov's work harnesses the exciting recent development of first-of-their-kind models for understanding two key aspects of human communication: how the brain extracts voice-identity or meaning-related information; and the grammar of communicative sequences. Dr Petkov's group aims to clarify the evolutionarily conserved cognitive abilities that underpin human language, and to bridge the gap between studies in animals, typical humans and language-impaired individuals. This could provide unprecedented scientific insight into the brain pathways and neuronal circuit mechanisms supporting language-related cognitive abilities.
Professor Alison Simmons, University of Oxford
The function of NOD2 in health and Crohn's disease
The intracellular pattern-recognition receptor NOD2 is essential for defence against intracellular microbes, and polymorphisms in NOD2 are associated with the development of the inflammatory bowel disease Crohn's. Professor Simmons has shown that NOD2 activates autophagy to destroy intracellular microbes in a pathway that is defective in Crohn's disease, via the mitochondrial fission protein Drp1. She has three major aims in investigating aspects of NOD2 function: to define signalling to Drp1 with a view to understanding the mechanism of NOD2-mediated Drp1 activation, and to define targets for enhancement of this activity in Crohn's; to understand the influence of NOD2 on antigen presentation and the differences in T-cell responses to different commensal microflora in Crohn's; and to understand the role of NOD2 function in intestinal epithelial cells and how Crohn's-variant NOD2 affects intestinal barrier health.
Dr Barry Thompson, Cancer Research UK London Research Institute
Planar polarity and tissue morphogenesis
How tissue shape is determined during animal development is a major unanswered question in biology. Failure to correctly shape tissues during development can lead to birth defects. The Dachsous-Fat cadherin system of planar cell polarity is essential for determining tissue shape in animals. This system forms long-range gradients across epithelial tissues, which are then interpreted by cells, leading to the orientation of cell movement and division along a particular axis. Dr Thompson aims to identify novel molecules and mechanisms involved in the interpretation of these gradients and the orientation of planar polarity in Drosophila. In doing so he wishes to understand how genetic programmes can organise the shape of a developing tissue.
Professor Gordon Brown, University of Aberdeen
C-type lectins in antifungal immunity
Professor Brown's work has established that C-type lectin receptors are critical for protective antifungal immunity. However, there is still much to discover in terms of the roles of these receptors and their therapeutic potential. During his award, Professor Brown will build on his exciting recent observations to investigate in detail how C-type lectins facilitate immune recognition and responses to fungi and how these responses can be both beneficial and detrimental to the host.
Professor Jonathan Clarke, King's College London
Cellular and molecular regulation of early brain development
The remodelling of cell shape and cell-cell junctions is of fundamental importance during the morphogenesis of many body organs. As well as being critical to building an embryo, misregulation of these processes may underlie serious disease states such as cancer, where cell behaviour is remodelled with potentially disastrous consequences. Professor Clarke aims to understand the cell biology of individual cells in the relatively complex environment of a living embryo's brain. Specifically, he will address how progenitor-cell shape and connectivity are remodelled during the morphogenesis and neurogenesis of the brain. The development of neuron morphology is of fundamental importance as it is one of the major factors that can contribute to neuronal connectivity and hence brain function.
Professor Antony Galione, University of Oxford
Two-pore channels and NAADP-mediated endolysosomal Ca2+ signalling in health and disease
Calcium ions are important signalling molecules regulating a multitude of processes, from fertilisation to cell death. Different stimuli and their combinations generate specific spatiotemporal calcium signals, which are decoded into distinct cellular responses. Cracking this code requires a detailed understanding of the spatial and temporal choreography of the messengers, proteins and organelles that generate these calcium signatures. Nicotinic acid adenine dinucleotide phosphate (NAADP) is unique in evoking calcium release from acidic endolysosomes, and recent work suggests that two-pore channels (TPCs) - a novel family of endolysosomal channels - are the target calcium channels for NAADP. Professor Galione's research aims to clarify fundamental aspects of NAADP signalling, particularly mechanisms by which cellular stimuli induce changes in NAADP levels, how NAADP mobilises calcium from the endolysosomal stores (particularly the precise roles of the TPCs), and the specific roles of endolysosomal calcium stores in (patho)physiological processes.
Professor Karim Labib, University of Dundee
Functional dissection of the eukaryotic replisome
One of the most important challenges for proliferating cells is to make a single and precise copy of each chromosome before cell division. This is achieved by a complex molecular machine called the replisome. Professor Labib aims to identify and understand the unique features of the eukaryotic replisome that are critical for the duplication and stable inheritance of eukaryotic chromosomes, but which are not shared with the much better characterised replisome of E. coli. A stronger understanding of chromosome replication is important: defects in chromosome replication are an early feature in the pathogenesis of cancer, and so may provide a target for the future development of new therapies to selectively target cancer cells.
Professor Leon Lagnado, University of Sussex
Synaptic computation in the visual system
Professor Lagnado will be using his Investigator Award to study how the retina and visual cortex carry out computations that are important for our sense of vision, such as detecting changes in contrast or estimating the orientation of an object. He will ask how these computations are modified in response to changes in visual input that lead to adaptive changes in processing, and in response to neuromodulators that alter circuit function on longer timescales. He is particularly interested in defining the roles of excitatory and inhibitory synaptic connections during these processing tasks. A feature of his approach is the imaging of activity across large populations of synapses and neurons. His guiding hypothesis is that the plasticity of neurotransmission plays a major part in altering the input-output relation of sensory circuits. The insight provided by this research will help us understand fundamental mechanisms by which neural circuits process information from a changing world.
Professor Juan Martin-Serrano, King's College London
Exploring the final events in eukaryotic cell division
Professor Martin-Serrano's research is focused on understanding how the last events in eukaryotic cell division are coordinated so as to prevent damage to any lagging chromosomes. The physical separation of daughter cells, termed abscission, is a fundamental process in biology that occurs as the final cytokinetic event, as it results in the physical cleavage of the midbody that forms between daughter cells. Professor Martin-Serrano is studying the mechanism that promotes midbody abscission, and how this process is regulated by a checkpoint process called NoCut, which can delay abscission where necessary to prevent genetic damage. His overall aim is to identify the molecular mechanisms underlying this process.
Professor Walter Marcotti, University of Sheffield
The development and function of the mammalian auditory circuitry
Professor Marcotti is studying how the auditory system develops and operates normally, and how defects at the molecular level can lead to deafness. He is doing this by investigating the physiological properties of the individual sensory hair cells of the mammalian cochlea, using electrophysiological, calcium-imaging and molecular-biology techniques. He will apply these techniques to unravel the physiological and genetic mechanisms that lead to the assembly of the proteins required for sound encoding, and, in so doing, aims to discover how inner hair cell synapses control the transfer of sound information to auditory fibres in vitro and in vivo.
Professor D James Nokes, University of Warwick
Defining pathways of respiratory virus transmission leading to improved intervention strategies
The transmission dynamics of human respiratory viruses are fundamentally linked to the organisational structure of person-to-person contact throughout a population, whether at the household, school, local community or national level. Professor Nokes aims to uncover potential pathways of transmission determined by contact structures, so as to gain greater insight into the emergence, spread, persistence and control of major viral causes of respiratory disease, including influenza, respiratory syncytial virus, coronaviruses and rhinoviruses. Using a framework for surveillance of respiratory infection at all organisational levels throughout the population of Kenya, for the first time temporal-spatial data on four respiratory viruses or virus groups will be coupled to whole-virus genome-sequencing data and data on social contact networks. The aim of this is to predict the most probable transmission routes in the population and to drive mathematical models to be used in exploring the effectiveness of targeted interventions, e.g. household- or school-based.
Professor Kate Storey, University of Dundee
Cellular and molecular mechanisms regulating neuronal differentiation in embryos and adults
Professor Storey is interested in the regulation of neuronal differentiation. She has recently discovered a novel form of cell subdivision, which involves local actin-myosin-mediated abscission of the apical cell membrane in cells poised to undergo neuronal differentiation in chick and mouse embryos. This process also involves the separation of apically positioned centrosome and cilium, and underlies the abrupt loss of apico-basal polarity and cell signalling at the onset of neuronal differentiation. Professor Storey plans to investigate how apical abscission is controlled, how centrosome and cilium separation is regulated and how these processes impacts upon cell signalling. A better understanding of the underlying mechanisms of neuronal differentiation and how these can be manipulated will inform strategies for treatment of neuronal injury and disease.
Professor Christoph Tang, University of Oxford
Bacterial immune evasion
Neisseria meningitidis continues to be a serious pathogen and is the leading cause of meningitis in children. The main aims of Professor Tang's research are to understand the mechanisms that enable Neisseria meningitidis to evade host immunity, the implications of this important pathogen surviving in the human nasopharynx, and subsequent disease in individuals. Professor Tang's approach is to dissect the molecular mechanisms underlying the virulence of this important human pathogen and to analyse the dynamics of carriage of meningococcus and other members of the flora of the human nasopharynx.
Dr Abigail Tucker, King's College London
Consequences of the dual origin of the middle ear epithelium on function
The mammalian middle ear is an air-filled space, lined with an epithelium, that houses three small bones called ossicles, which conduct sound from the eardrum to the inner ear. Previously, it was thought that the lining of the middle ear was entirely endoderm-derived. However, Dr Tucker's recent work shows that the lining has a dual origin, as part of the middle ear is lined with neural crest cells that undergo a mesenchymal-to-epithelial transformation. She now aims to understand the normal development of the middle ear - and how defects during development have an impact on the function of the ear - by identifying the signals involved in this mesenchymal-to-epithelial transformation. In addition, she wishes to understand the consequence of the dual origin of the epithelium on susceptibility to ear infection (otitis media) and the development of middle-ear cysts (cholesteatomas), both major problems in the middle ear.
Professor Andrew Wilkie, University of Oxford
Mutations in malformation and disease
Professor Wilkie's research focuses on the mutational processes that cause malformation and disease. By employing high-throughput DNA sequencing, it is now possible to obtain an unbiased inventory of mutations relevant to serious human diseases. Using this information, Professor Wilkie aims to investigate two different but complementary disease areas, in both of which the contributions of single gene mutations are well-established but the inventory of mutations is incomplete. These are craniosynostosis, which is the premature fusion of the cranial sutures, and mutations enriched in normal testes and sperm. One overall goal is to identify all monogenic causes of craniosynostosis, which cause the disease in about one quarter of affected individuals. In addition, pathogenic mutations in sperm will be explored through a novel disease process, termed selfish spermatogonial selection, which has been delineated in Professor Wilkie's laboratory. This will enable the identification of the molecular pathways in the testis that are vulnerable to this process.
Professor Nikolay Zenkin, Newcastle University
Transcription: from catalysis to cellular regulation
Transcription is a critical process in biology, but many of the details underlying key events of the transcription cycle, as well as its regulation, are yet to be uncovered. Professor Zenkin is studying enzymology and the regulation of RNA polymerase - the enzyme that produces the RNA transcript from a DNA template. This research draws on methods from classical biochemistry and molecular biology, as well as some novel and unique experimental systems. In the long term, an understanding of the mechanisms of bacterial transcription may provide the basis for the design of effective antimicrobial agents.
Professor Anne Dell, Imperial College London and Professor Brendan Wren, London School of Hygiene and Tropical Medicine
Deciphering the bacterial glycocode
Glycoproteins are ubiquitous biomolecules involved in many biological processes ranging from immunity recognition to cancer development. In eukaryotes, glycosylation is known to impart novel biological and physical roles by providing labels for cell-cell communication and assisting in protein stabilisation. However, the role of glycosylation in bacteria and pathogenesis remains poorly understood. Recent evidence for protein glycosylation being central to the survival and pathogenesis of many bacteria suggests it is an ideal target for disabling them. Professors Dell and Wren will investigate the molecular, structural and functional basis of glycosylation in pathogenic bacteria, which will provide new avenues for antibiotic and vaccine design.
Dr Peter Magill, University of Oxford
Functional dichotomy in the external globus pallidus
The external globus pallidus (GPe) is a key component of the basal ganglia, a network of brain regions critical for motor control and the learning of routine behaviours. It has long been thought that the neurons of the GPe are a relatively homogenous population, but recent evidence suggests that it is instead made up of dichotomous neuronal groups. Dr Magill will address the necessity for and nature of this dichotomy in the GPe. In elucidating the substrates for GPe neuron specialisation at different scales of function, he aims to provide explanations in the context of whole-brain function and behaviour.
Professor Mohan Balasubramanian, University of Warwick
Using a permeabilised cell system and cell physiology to understand cytokinetic actomyosin ring constriction
Professor Balasubramanian’s research focuses on understanding eukaryotic cytokinesis mechanisms. Cell division involves an actomyosin-based contractile ring - containing the contractile proteins actin and myosin - which constricts following chromosome segregation to divide one cell into two. However, very little is known about the mechanism of ring constriction and force generation. Professor Balasubramanian intends to research how the actomyosin ring constricts and generates force, and what role myosin II plays in this process. In addition, he aims to establish whether force-generation mechanisms independent of myosin II are involved in actomyosin ring constriction and cell division. Furthermore, he intends to investigate what mechanisms ensure that actomyosin ring constriction is initiated only after segregation of chromosomes. Because actomyosin contractility is central to numerous cellular processes, ranging from wound healing and cell migration to asymmetric cell division and stem cell development, this work will potentially have an impact on a broad range of fields.
Professor Michael Ferguson, University of Dundee
Protein glycosylation in trypanosomes: defining and exploiting a biological system
Professor Ferguson works on glycoprotein structure and biosynthesis in parasites, particularly Trypanosoma brucei, the causative agent of human African sleeping sickness. As part of their strategy to survive inside parasitised hosts, the trypanosomes depend on a coat of surface glycoproteins (proteins with sugar chains attached). Glycoproteins perform many vital functions for the parasites with respect to their infectivity and survival in hosts. These include nutrient uptake, endosome/lysosome function, flagellar adhesion and, above all, hiding themselves from the hosts’ immune systems. Professor Ferguson plans to provide a complete understanding of the range of glycoprotein structures made by Trypanosoma brucei and to use the findings as a road map to define the biosynthetic machinery that allows the parasite to assemble them. This knowledge will help identify potential drug targets for translation into drug discovery for sleeping sickness and related parasitic infections.
Professor Frederic Geissmann, King’s College London
Professor Geissmann will seek to understand the role that macrophages play in homeostasis, with a particular focus on their role in metabolic diseases such as type 2 diabetes, cardiovascular diseases and inflammatory diseases. The mechanisms underlying the role of macrophages are incompletely understood, in part due to the heterogeneity of macrophages in vivo. One of Professor Geissmann’s aims will be to understand the functional differences between the myb-dependent and myb-independent macrophage lineages, the latter having been described by him in 2012. He will analyse the contribution of these two lineages to inflammation and foam cell formation using mouse models, and undertake genetic analyses of macrophage responses to a lipid-rich diet using Drosophila.
Professor Neil Gow, University of Aberdeen
Making and breaking the cell walls of fungal pathogens
The cell wall of fungal pathogens determines their pathobiology and immunological signatures. It is a target for chemotherapies and immunotherapies because the major cell wall components are essential and fungal-specific. Professor Gow wishes to understand how the cell wall is assembled and how it is recognised by the immune system. He will investigate key assembly processes and functions of the extended gene families that articulate the cell wall, and deploy novel screens, phenotyping methods and in vitro synthetic biology approaches to dissect the functions of important genes. The programme will also define the chemical structure of cell wall molecules that stimulate, attenuate and imprint the innate and adaptive immune responses. Host and pathogen functional analysis tools will be used to study the immunologically relevant cell wall glycoconjugates. These complementary approaches should advance our understanding of therapeutically tractable targets of the cell wall and will inform the design of new therapeutics and diagnostics.
Professor Erhard Hohenester, Imperial College London
Molecular mechanisms of laminin function in health and disease
Laminins are the major cell-adhesive proteins of basement membranes, the archetypal form of extracellular matrix that is required for tissue formation. Genetic defects in laminins and their cellular receptors cause serious skin blistering diseases, muscular dystrophies and kidney disorders. Yet three decades after the discovery of laminins, we still lack a mechanistic understanding of their iconic functions: polymerisation and cell adhesion. Professor Hohenester’s research aims to address these important unresolved questions through a combination of structure determination and biochemical validation. A better understanding of the molecular mechanism of laminin binding to integrins should aid in the development of new reagents for tissue engineering and stem cell culturing.
Professor Vassilis Koronakis, University of Cambridge
Towards a high-definition view of cytoskeleton remodelling by the bacterial pathogen Salmonella
Professor Koronakis is fascinated with molecular events at biological cell membranes, encompassing the structure and function of bacterial multidrug efflux pumps, and the action of bacterial effectors that seize control of host cells to force pathogen invasion. He aims to study mammalian cell-membrane signalling pathways that are vital to the control of cytoskeleton remodelling in health and infectious disease. He will combine his innovative experimental approach to study membrane signalling platforms in vitro, with his work showing how effectors of the pathogen Salmonella subvert regulatory control of the host cell cytoskeleton. This will focus on the WAVE regulatory complex, one of the cell’s key regulators of actin assembly and cell shape, and how it is controlled by cooperating Arf and Rac GTPases. This fusion of biochemistry and cell biology promises a greater understanding of key signalling processes in our cells, and new insights into how bacteria establish infection.
Professor Mala Maini, UCL
Immunopathogenesis and immunotherapy of viral hepatitis
Hepatitis B virus (HBV) remains one of the most frequent causes of death worldwide, resulting in around 600 000 deaths annually from liver cirrhosis and hepatocellular carcinoma. Professor Maini has recently elucidated new pathways by which HBV exploits the tolerogenic hepatic environment to subvert antiviral immunity and promote liver disease. The objective is to build on this work by defining key molecular mechanisms that can be blocked in order to develop novel immunotherapeutic approaches to treat chronic HBV infection. Professor Maini has three interrelated aims: to investigate the capacity of hepatic antigen presenting cells to tolerise T cells; to explore the pathogenic and protective roles of NK cells in the liver; and to develop approaches to promote the survival and function of HBV-specific T cells generated by vaccination or immunotherapy.
Professor Gilean McVean, University of Oxford
The genetic analysis of populations
Professor McVean’s research uses patterns of genetic variation among individuals to answer questions about fundamental biological processes, the nature of evolutionary processes, and the link between genetic variation and an organism’s observable characteristics or detectable traits. His research aims to develop statistical and computational tools to integrate de novo sequence assembly and multiple reference sequences to best characterise the genome sequence(s) of an individual or of diverse species (such as malarial parasites). These tools will also be used to define key genomic regions (such as the HLA region) from human sequencing data and to reliably identify diverse genome-changing events from whole-genome sequence data of individuals in extended pedigrees. The genetic structure of the HLA region in different populations will be assessed to explore how variation influences the immune response to, and risk of, infectious and autoimmune diseases.
Professor Markus Müschen, Institute of Cancer Research
Negative feedback and oncogene signalling in leukaemia
Tyrosine kinase inhibitors (TKIs), used against cancer-promoting (oncogenic) tyrosine kinases, have created a new era of treatment for patients with leukaemia and solid tumours. Despite their clinical success in chronic myeloid leukaemia, TKI resistance is a common outcome in almost all other malignancies. Research has uncovered an unexpected dependence of tumour cells on negative feedback regulation of signalling pathways downstream of oncogenic tyrosine kinases. Professor Müschen aims to build a fundamental understanding of: why tyrosine-kinase-driven cancer cells are uniquely sensitive to loss of negative feedback; whether tyrosine-kinase-driven cancer cells can only thrive within the limits of a ‘comfort zone’ of oncogene signalling, with either attenuation (TKI) or hyperactivation (blockade of feedback) leading to cell death; and how ablation of negative feedback mechanistically leads to cell death. He then aims to leverage this information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and inhibitors of feedback.
Dr Jonathan Roiser, UCL
Neural and cognitive processes in depression
Depression is a debilitating illness and represents a major public health problem, with a heavy economic and social burden. Dr Roiser will use neurochemical, neuroimaging and behavioural techniques to understand the cognitive and neural mechanisms underlying depression, which his previous work suggests exist prior to the onset of symptoms and independent of medication effects. Dr Roiser aims to examine how abnormal processing of positive outcomes (‘rewards’) and negative outcomes (‘punishments’) contributes to particular depressive symptoms, whether this processing is also abnormal before and after an episode of depression, and how it is affected by levels of the brain chemical dopamine. His long-term goal is to provide a testable neuroscientific account of the brain mechanisms underlying depression. In the long term this approach has the potential to improve patient outcomes by moving away from a descriptive level of diagnosis towards a mechanistic approach to classification and treatment.
Professor Colin Taylor, University of Cambridge
Spatial dynamics of receptor-regulated calcium signalling
Professor Taylor’s research will investigate calcium signalling, with a particular focus on the structure and behaviour of intracellular inositol trisphosphate receptors. The key question to be addressed is how dynamic organelles and proteins mediate communication between extracellular stimuli and the calcium signals that regulate many cellular activities. These signalling pathways must be specific and sensitive and respond with appropriate speed. A handful of diffusible messengers, including cAMP, calcium and inositol trisphosphate, selectively transmit information from G-protein-coupled receptors (GPCRs), which are activated by diverse extracellular stimuli, to numerous cellular responses. Inositol trisphosphate receptors respond to many of these messengers, generating calcium signals that regulate cellular activity. Defining the dynamic architecture of these signalling pathways is essential to understanding how specificity is maintained as information passes speedily from GPCRs to responses, and to identifying drug targets that might disrupt this communication.
Professor Anton van der Merwe, University of Oxford
Immune recognition by non-catalytic tyrosine-phosphorylated receptors
Professor van der Merwe’s research aims to increase our understanding of the molecular and biophysical rules governing recognition by leukocyte receptors, a process that underpins immune responses. He has generated important biophysical data on the interactions that occur between T-cell antigen receptors (TCRs) and their surface-anchored ligands, and has demonstrated that the sizes of the molecules involved in the formation of the immunological synapse play a key role in the resulting signalling outcome. This has led him to propose a novel model of TCR triggering called the kinetic-segregation (K-S) model. Recently he has proposed that other leukocyte non-catalytic tyrosine-phosphorylated receptors (NTRs) are also triggered by the K-S mechanism. Professor van der Merwe will now address three main aims: to determine the mechanism of NTR triggering upon ligand binding; to explore how NTRs integrate their signals with each other and with other receptors; and to elucidate the mechanisms driving, and functional consequences of, NTR aggregation into clusters.
Professor César Victora, Federal University of Pelotas, Brazil
Global observatory of trends and inequalities in child health and nutrition
Expanding on his experience monitoring inequalities in reproductive, maternal, newborn and child health in low- and middle-income countries, Professor Victora will build up a global data platform on health inequalities to address important scientific questions with direct practical implications for country- and global-level decision makers. He aims to systematically analyse levels and trends in population subgroups, with a focus on maternal and child health and nutrition. Specifically, he will examine the monitoring of child health indicators, interpretation and evaluation of recent trends in health and nutrition, develop forecasting of long-term consequences on child health and nutrition, and investigate how findings can be rapidly and effectively disseminated to promote evidence-based decision-making.
Professor Waldemar Vollmer, Newcastle University
Bacterial cell wall synthesis and degradation
Professor Vollmer studies the structure and biosynthesis of the bacterial cell wall that protects the cell from bursting due to internal osmotic pressure, and that maintains the cell’s specific shape (spherical, rod-shape, helical, etc.). Bacterial cell wall synthesis is targeted by important classes of antibiotics, such as the beta-lactams and glycopeptides. Little is known about how bacteria enlarge their cell wall when they are growing and dividing. This research aims to decipher the molecular mechanisms of cell wall growth in Gram-negative bacteria, which have an outer membrane, including the model bacterium Escherichia coli and important pathogens like Pseudomonas aeruginosa and Helicobacter pylori. Professor Vollmer will study the interactions and activities of cell wall synthesising and degrading enzymes, which presumably form dynamic multi-enzyme complexes catalysing cell wall growth. This could lead to new strategies for interfering with bacterial cell wall synthesis, with the potential for the development of novel antibiotics.
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
The interferon (IFN) system is a major component of vertebrate innate antiviral immunity. It is so powerful that most (if not all) viruses have evolved IFN antagonists. Whilst there has been an explosion in our knowledge of this subject in the last 10-15 years, there are still many unanswered questions about how viruses interact with the system. Professors Goodbourn and Randall aim to build up a comprehensive understanding of this interaction by focusing on paramyxoviruses, an important group of human and animal viruses that includes measles, mumps, parainfluenza and Newcastle disease viruses. Their studies will investigate: how paramyxovirus infections trigger IFN production; whether overstimulation of the system (and other innate responses) exacerbates disease processes; how IFN controls paramyxovirus infections and influences virus host range, pathogenicity and persistence; and the potential application of their findings to improve the control of virus diseases.
Dr Jake Baum, Imperial College London
The cellular and molecular mechanics of malaria parasite invasion of the human erythrocyte
Dr Baum’s programme of research aims to address key questions in understanding how malaria parasites (Plasmodium species) invade the red blood cell - a critical step in the pathogenesis of malaria disease. The focus of the programme is aimed at every level of investigation, from atomic resolution of the parasite motor and single-molecule biophysical dissection of parasite motor force, to fixed and live imaging of parasite cells on the move. Dr Baum will be combining each of these approaches with comparative Plasmodium biology and, critically, inclusion of the host erythrocyte cell biology, towards the ultimate goal of understanding key events in parasite invasion and the identification of weaknesses that can be targeted to stop it.
Dr Lindsay Hall, University of East Anglia
Role of early-life gut microbiota in colonisation resistance development
Complex microbial communities (microbiota) colonise the body after birth. These beneficial bacteria shape immune defence, limiting infection by gut pathogens through a process of colonisation resistance. However, disturbances such as caesarian sections and antibiotic exposure in early colonisation events can lead to increased susceptibility to pathogens, as well as allergic and chronic inflammatory diseases in later life. Dr Hall will work on building our knowledge of the contribution of specific bacterial species during early-life development, and how microbiota disturbances increase susceptibility to gut infection, focusing on bifidobacteria. The goals are to understand the effects of bifidobacteria on critical colonisation resistance, the impacts of antibiotic-induced disturbances, and the potential for restoring a disturbed early-life microbiota to control gut infection, for use in infectious-disease settings.
Dr Matthew Higgins, University of Oxford
Structural studies of host-parasite interactions at the heart of malaria pathogenicity
Proteins on the surface of the malaria parasite are at the front line of its battle with the host. Dr Higgins’s project will use the latest tools to determine structures of protein-ligand complexes involved in red blood cell invasion and placental sequestration in pregnancy-associated malaria. Structural studies will allow mapping of polymorphisms onto molecular surfaces while identifying conserved binding sites and inhibitory epitopes on which to focus. An insight into the molecular structure of key malaria surface proteins will guide design of future vaccine components.
Dr Jack Mellor, University of Bristol
The role of acetylcholine in hippocampal function
The mechanisms by which the neurotransmitter acetylcholine enhances cognition are not fully understood. Dr Mellor will be working towards defining the cellular, synaptic and network effects of acetylcholine in the hippocampus and determining its role in cognition. He will focus on which acetylcholine receptors regulate synaptic plasticity and neural network activity using a multidisciplinary approach. The aim is to define ways to pharmacologically modulate the hippocampal network.
Dr Nicholas Morton, University of Edinburgh
Functional characterisation of the novel adipocyte lean gene thiosulphate sulphurtransferase: developing next-generation obesity therapeutics
Obesity is a major global health problem. Its chronic disease complications (type 2 diabetes, hypertension, atherosclerosis and certain cancers) are the major causes of morbidity and mortality in developed and, increasingly, developing countries. Dr Morton’s vision is that genes promoting healthy leanness in the face of genetic and intense environmental obesity-causing pressures represent important biology and an untapped source for anti-obesity therapeutics. He has identified the enzyme thiosulphate sulphurtransferase (TST) as one possible candidate for driving healthy leanness. Dr Morton’s work will investigate the mechanism of action of TST. He will specifically test the hypothesis that TST augments mitochondrial function, reduces mitochondrial oxidative/metabolic stresses and thereby improves adipocyte function and release of anti-diabetic adipokines. It is hoped that by understanding the role of TST, it may be exploited to ultimately treat obesity and its related metabolic problems.
Dr Jan Rehwinkel, University of Oxford
Cytosolic DNA sensing in infection and autoimmunity
Dr Rehwinkel’s programme of research aims to further our understanding of cytosolic DNA detection by the host immune system. Cytosolic DNA detection is important not only during many bacterial and viral infections, but also in autoimmune and autoinflammatory diseases and DNA vaccination. However, the signalling pathways that detect DNA in the cytosol and in particular the DNA sensors triggered by cytosolic DNA remain unknown or incompletely understood. Dr Rehwinkel plans to identify cytosolic DNA sensors and their downstream pathways, establish new models for studying DNA sensors, and define the role of cytosolic DNA sensing during autoinflammation and infection.
Dr Jessica Strid, Imperial College London
Lymphoid stress-surveillance - linking tumour immunesurveillance and atopy
The overarching aim of Dr Strid’s programme of work is to characterise and explore lymphoid stress-surveillance (LSS). Described by Dr Strid, this is the activation of local intraepithelial lymphocytes, by physico-chemical tissue damage, that in turn initiates local and systemic Th2 and IgE responses as well as anti-tumour immunity. Key goals of the research are to investigate fundamental aspects of LSS and to determine the role of early LSS-induced Th2 immunity and IgE antibodies in epithelial dysregulation and carcinogenesis. The results will shed new light on the afferent induction of Th2 immunity and will further our understanding of the biological relationship between allergy and cancer.
Professor Sivaramesh Wigneshweraraj, Imperial College London
Non-bacterial regulators of bacterial transcription
The widespread global emergence of bacteria resistant to antibiotics necessitates research into novel antibacterial drugs and drug targets. Bacteriophages, viruses that infect and destroy bacteria, have evolved numerous ways to arrest essential bacterial processes such as DNA transcription and replication, in order to successfully take over the bacterial host for bacteriophage reproduction. The methods employed by bacteriophages represent a new toolbox to inform and inspire novel antibacterial drug and drug target discovery. Professor Wigneshweraraj will focus on research into bacteriophage-derived inhibitors of bacterial RNA polymerase, the enzyme responsible for all RNA synthesis in bacteria.
Professor Luis Aragon, Imperial College London
Functional dissection of mitotic chromatin
The compaction of chromosomes as cells enter mitosis is probably the most iconic process of dividing cells and represents one of the most fundamental biological processes, yet it is poorly understood. Recent work from Professor Aragon demonstrated that minichromosomes in yeast cells undergo a change characterised by an overwinding of the DNA double helix that is mediated by the condensin complex as chromosomes are compacted. Since nucleosomes impose underwinding on DNA, the observation implies that the distribution and/or conformation of nucleosomes must be altered during mitosis. This realisation provides a radical departure from the view that mitotic nucleosomes are a passive factor during chromosome assembly. Professor Aragon is aiming to investigate the nature and functional role of the histone component of mitotic chromosomes and to uncover the mechanisms by which histones contribute to chromosome condensation.
Professor Jorge Ferrer, Imperial College London
Understanding regulatory variation in human diabetes
It has recently become apparent that a major fraction of the human genome contains functional regulatory elements. Several studies have demonstrated that sequence variation in noncoding genomic elements can cause Mendelian disorders, and it is widely thought that these noncoding elements are critically important for susceptibility to common complex diseases. Professor Ferrer aims to provide tools to understand how noncoding variants disrupt regulatory functions that cause Mendelian diabetes or type 2 diabetes susceptibility. He will also aim to exploit human genetics to discover novel genome regulatory mechanisms, in analogy to how genetics has revealed unanticipated protein functions underlying beta-cell development and function.
Professor Matthew Freeman, University of Oxford
The control of signalling by members of the rhomboid-like superfamily
Professor Freeman plans to investigate how intercellular signalling is controlled in order to regulate nearly every facet of human physiology. Professor Freeman and his team have recently discovered that proteins of the rhomboid-like superfamily (polytopic membrane proteins related to rhomboid intramembrane proteases, most of which, however, lack protease active sites) act as regulatory adapters to control the fate of growth factors and cytokines, as they are trafficked through the cell. He will examine the molecular and cellular mechanisms by which rhomboid-like proteins determine the fate of signalling proteins, discover how rhomboid-like proteins are influenced by physiological cues, and determine their physiological significance and relevance to human disease. The further understanding of these rhomboid-like proteins may lead to the development of future therapeutic strategies.
Professor Sir John Gurdon, University of Cambridge
Mechanisms for the reprogramming of somatic cell nuclei by eggs and oocytes
Eggs have a remarkable ability to rejuvenate the nucleus of a differentiated (or adult) cell to provide a source of normal embryonic stem cells. Such cells have enormous potential for making disease-specific cultured cells for drug testing and possibly for cell replacement therapy. Nuclear transfer to eggs and transcription-factor-induced pluripotency are routes by which this rejuvenation of differentiated cells, and hence somatic cell reprogramming, can be achieved. Professor Gurdon will investigate which natural components of eggs and oocytes can achieve nuclear reprogramming and how differentiated cells resist reprogramming. It is hoped that examining the mechanisms by which differentiated cells are stable and resist reprogramming will help to explain the processes that, when defective, can lead to disease or cancer.
Dr Frederick Livesey, University of Cambridge
Human stem cell models of Alzheimer’s disease
Dementia is a major healthcare challenge that currently affects about 36 million people worldwide. Alzheimer’s disease (AD) is the most common form of dementia, accounting for over 60 per cent of cases, yet there are currently no licensed drugs that modify the course of the disease. Dr Livesey plans to build on his previous work, which led to the development of stem cell models of AD, to generate insights into AD initiation, progression and therapeutic intervention. Specifically, he will investigate how AD progresses and spreads through the human nervous system, and how AD affects neuronal function at the synapse and network level. He will also study AD-associated genetic variants and how these contribute to disease initiation and progression in sporadic, late-onset AD. By examining the causes and mechanisms of AD initiation and progression, it is hoped that these can be reversed and that new therapeutic interventions can be developed.
Dr Andrew McKenzie, University of Cambridge
Innate lymphoid cells in immunity and disease
Following the recent discovery of innate lymphoid cells (ILCs), it was determined that these cells are critical regulators of protective immunity against parasitic helminths and bacteria and also in autoimmune disorders. Dr McKenzie aims to investigate the biological roles of ILCs and to elucidate their developmental relationships within the lymphoid lineage and their functional roles in protective immunity and disease. The aim is to build on existing knowledge of type 1 and type 2 disease models, and their dissection using molecular genetics in mice, to provide new insight into these pathways and identify potential therapeutic targets.
Professor Jeffrey Pollard, University of Edinburgh
The metastatic cascade: macrophages lead the way
In breast cancer, the survival rate of women with metastatic disease has not changed for 30 years, indicating the need for different treatment strategies. While research has largely focused on tumour cells, it has become apparent that, in tumour progression to malignancy, progressive modification of the stromal microenvironment is as important as the changes in the tumour cells themselves. The aim of Professor Pollard’s research is to define the molecular basis of how macrophages promote tumour progression to malignancy. Specifically, he will investigate how macrophages stimulate angiogenesis, promotion of tumour cell invasion and intravasation, suppression of anti-tumour immune responses, and promotion of extravasation at metastatic sites and their subsequent tumour cell establishment and persistent growth. It is hoped that this research will identify new pathways and targets for therapeutic intervention in human breast cancers.
Professor Barry Potter, University of Bath
Chemical biology of cellular signalling using polyphosphate messengers
Different cells can communicate via chemical messengers, such as hormones and neurotransmitters, and the malfunction of cell-signalling pathways often underlies disease. Such 'first messengers' generally interact with a cell surface receptor, and small-molecule 'second messengers' subsequently carry this signal to internal effector proteins to coordinate a response. Professor Potter will use the techniques of chemical biology, employing synthetic and biological chemistry, to explore the application of tailored synthetic signalling tools in investigative biology. His prime focus is on messengers possessing multiple phosphate groups that dynamically mobilise cellular calcium, such as the cyclitol polyphosphate IP3, and also on newer signalling nucleotides such as cADPR, NAADP and ADPR, and the enigmatic higher inositol polyphosphates. Designing chemical tools for the modulation of these polyphosphatases by changing molecular structure, in concert with other interdisciplinary techniques and as part of a process informed by structural biology, will provide both targeted tools for the interrogation of cell-signalling mechanisms and early leads for potential drug candidates.
Professor Matthew Rushworth, University of Oxford
Neural mechanisms for foraging in an uncertain environment
Professor Rushworth’s research is motivated by the idea that some aspects of human decision-making may best be understood using principles from animal foraging behaviour. To test this ‘ecological’ model, he will employ a range of novel tasks that seek to understand how humans identify what options are available in the environment and how their choices are guided by contextual factors (e.g. short- versus long-term goals). To understand which brain regions are involved in these processes, Professor Rushworth will combine computational modelling with functional magnetic resonance imaging (fMRI). He will also use transcranial magnetic stimulation to gain insight into how disrupting activity in parts of the decision-making network influences activity in other regions.
Professor Brigitta Stockinger, National Institute for Medical Research
Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor recently shown to play an important role in the immune system, although mechanistic insight is limited. Professor Stockinger plans to investigate the physiological functions of the AhR in the immune system. The programme of work includes: identifying protein interactions with AhR in different cell types and immunological conditions using AhR-FTAP mice; investigating the physiological regulation of AhR signalling via metabolic enzymes; analysing mice with cell-type-specific AhR deletions in order to identify cell-intrinsic consequences of defective AhR signalling; and testing the hypothesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barrier sites.
Professor John Wood, University College London
Peripheral pain pathways
There is a clinical need for a better understanding of pain in order to develop new drugs. Professor Wood has shown previously that different sets of sensory neurons evoke distinct pain sensations. During this Award, he will use a genetic approach and employ novel transgenic mice to define the sets of peripheral sensory neurons responsible for distinct pain sensations and to investigate how these neurons transmit information to the central nervous system. His aim is to identify the mechanisms and molecules associated with distinct pain sensations, focusing on mechanical and cold allodynia and visceral pain. He will also investigate the contribution of sensory neurons, normally associated with innocuous sensations, to pain sensations in neuropathic pain states.
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.
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
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
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.
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
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.
Dr James Briscoe, Division of Developmental Biology, MRC National Institute for Medical Research
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.
Dr John Christodoulou, University College London
Structural biology of protein folding on the ribosome
Dr Christodoulou studies the co-translational folding process, which transforms a nascent polypeptide chain into a fully folded and functional protein as the chain emerges from the ribosome (the protein synthesis machinery in cells). His research will look at the structure and dynamics of nascent proteins during their synthesis, how they interact with the ribosome and molecular chaperones (proteins that aid folding) and how the ribosomal machinery aids trafficking to the correct cellular compartment. This knowledge of how protein three-dimensional structures arise or misfold is important in a range of metabolic, oncological and neurodegenerative conditions.
Professor 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.
Professor Derek Jones, Cardiff University
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.
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
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.
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.
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
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.
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
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
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.
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, University College London
Integration of internal and external signals in sensory cortex (joint award with Professor Carandini)
Professor Harris’s research focuses on the mechanisms by which populations of cells in the brain form information-processing assemblies. In conjunction with Professor Carandini, Professor Harris will employ his award to understand how the brain integrates multiple signals, applying a computational approach to model neuronal signal interactions in the cortex.