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Results

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigate the role of SET1A in the activation of gene expression 30 Sep 2018

The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of the host-parasite interactions at the heart of malaria pathogenicity 05 Apr 2018

Our proposed activities consist of two major strands. Firstly we wish to take our research on tour, developing a high quality interactive stall which will allow us to present our findings to those who visit science fairs. We have secured a place at the Royal Society Summer Science Exhibition in July 2018, as the first outing for our display and this provides the deadline by which we must have the stall in place. As this is one of the UK’s premier science festival, visited by ~13,000 people each year, this is a great opportunity to meet people and to share our research. We will also ensure that our stand is fully updateable in content – for example using interactive screens which can be altered over time. We will next present at the Oxford Science Festival in 2019 and 2020, at which the Biochemistry Department has committed space. We will also apply to present at another major science festival as soon as applications open (i.e. Cheltenham and Edinburgh) in each of 2019 and 2020. This will be supported by digital content, including a ~2 minute video which will describe our approach towards rational malaria vaccine design and will be posted on Youtube. We will also develop an interactive vaccine game in which players can allocate health budgets and see the effect on malaria prevalence. Together with informative content about our research, these will widen the accessibility of our research.

Amount: £49,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular Simulations of Membrane Protein Lipid Interactions 31 May 2018

Membrane proteins account for ca. 20% of all genes, 40% of drug targets, and are mutated in many human diseases. The past decade has witnessed an exponential rise in the number of high resolution membrane protein structures. Interactions with lipids are of crucial importance for the stability, regulation, and targeting of membrane proteins, but structural and biophysical data on membrane protein-lipid interactions remain sparse. Molecular dynamics (MD) simulations provide a key tool for probing the interactions of lipids with membrane proteins. The overall aim is to apply multiscale simulations to predict specific lipid interactions of lipids with recently determined cryoEM structures of selected membrane proteins. This will be achieved by a serial multiscale approach. Coarse-grained simulations will be used to identify the interaction of membrane proteins with the lipids of complex membranes (i.e. in physiologically relevant mixed lipid bilayers based on lipidomics data). Atomistic simulations will be used to refine the resultant models. Predictions of protein/lipid interactions will be tested experimentally via our collaborators.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

What Are The Roles Of MEIS1, BMI1 And HOXB Genes In Self-Renewal Of Acute Myeloid Leukaemia Stem Cells? 30 Sep 2018

Acute myeloid leukaemia (AML) is the commonest aggressive leukaemia in adults. Due to treatment resistance and relapse, the prognosis for most patients is poor. In normal blood cell development, stem cells are the most immature cells and can produce any type of blood cell. AML results when bone marrow cells acquire genetic alterations, called mutations. These mutations occur in early bone marrow cells and result in a ‘leukaemic stem cell’, which maintains growth of the leukaemia. Previous work in the Vyas laboratory has identified genes that are switched on in AML patients that cause leukemic stem cells to grow abnormally, including HOX genes. This project aims to further our understanding of the impact of these genes in leukaemic stem cells by answering questions such as: Is AML cell growth impaired when these genes are switched off? Do leukaemia cells behave like normal blood cells when these genes are switched off? Does switching on the genes make normal bone marrow cells behave like leukaemia cells? What mechanisms allow these genes to regulate the function of leukaemia cells? Our overall aim is to use this information to design treatment strategies to eradicate leukaemic stem cells.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular control of pathogenic neutrophil responses in inflammation 28 Nov 2017

Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.

Amount: £1,541,677
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanobiological control of immune cell activation 21 May 2018

Biomedical sciences increasingly recognise the importance of mechanobiology in health and disease. While most mechanisms of the immune response are adequately explained by cell-biology, biochemistry, and genetics, many of its features profoundly depend on biomechanical aspects. One such scenario involves the ability of immune cells to differently respond to antigens with similar binding affinities, highlighting additional parameters needed to fully explain antigen discrimination. Emerging evidence indicates that immune cells dynamically adjust their biomechanics to facilitate this process. The principle goal of this project is to uncover how biomechanical feedback modifies the mechanobiology of activating T-lymphocytes by altering the dynamic assembly and organisation of actin structures, hence adjusting the sensitivity of antigen recognition. With the advent of immune checkpoint blockade and T-cell re-direction there has never been more interest in controlling lymphocyte responses, and biomechanical signal integration has received relatively little attention despite the consistent failure of biochemical parameters to account for T-cell discrimination of different antigens. To address this research project, I will lead a team to apply new state-of-the-art force probing technology coupled with high-speed super-resolution microscopies, overcoming the limitations of previous approaches to generate a breakthrough understanding of mechanobiology in immune cell activation.

Amount: £98,263
Funder: The Wellcome Trust
Recipient: University of Oxford

The Effect of Priorizing Information in Working Memory on Later Behavioural Interference 31 May 2018

This experiment will investigate how prioritised information is represented in working memory (WM) through looking at the serial dependence effect. Myers and colleagues (2017) have suggested that items which are prioritised in WM are transformed into action-ready representations. Therefore, the theory predicts that the difference between prioritised and non-prioritised representations in WM will be reflected in behavioural findings. The serial dependence effect occurs when visual information from the recent past biases perception and behaviour at the present moment (Fischer & Whitney, 2014). If prioritised WM items were stored in an action-oriented format, we predict it will show these interference effects in behaviour more than non-prioritised information. By using an orientation adjustment paradigm, we will measure the serial dependence effect for prioritised WM items (which have been retro-cued) versus non-prioritised WM items. In addition, we will vary the type of testing (forced choice versus free recall), predicting that more interference will occur when the tests are the same than when different, due to the action-based nature of the WM representation. Initially we will use behavioural measures (reaction times) to measure the interference effects, extending to EEG to measure neural evidence for the carry-over effects.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

The Role of Cyclophilins in Innate Immunity 30 Sep 2018

The Cyclophilins are a widely expressed, broad acting family of proteins defined by their common enzymatic domain. Among their multiple roles, they are reported to be involved in viral infections (including HIV, Hepatitis, and Influenza infections) both to the benefit and the detriment of the host. Despite this, much is still unknown about whether they play a role in the innate immune system. In the past this research has been limited due to the broad reactivity of the innate immune cells. However, with recent progress in stem cell research and CRISPR gene editing technology, we are now capable of manipulating these cells far more effectively. Therefore I intend to use these advances to knock out each member of the Cyclophilin family and then challenge my cells with a range of immune stimulants looking for changes in innate cell activation and protein secretion. Combining my panel with a pharmacological approach targeting virus-cyclophilin interactions, I also intent to determine whether HIV-1 uses only Cyclophilin-A during infection and discover novel Cyclophilin interacting proteins. These studies aim to lead to a better understanding of the fundamental functioning of cells in response to various threats, and may lead to pathogen specific drug therapies targeting Cyclophilins.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Decoding the molecular identity of neurons 28 Nov 2017

Regulated gene expression underlies the specification of cell fate and the maintenance of cell-specific function. Cellular diversity is of particular importance in the brain where neural circuits are assembled from cells with unique properties. Many neurological and psychiatric conditions arise from dysfunction in the brain, and although molecules are the targets of therapeutic drugs, we know relatively little about those that are critical for specific neural functions. Here we propose to generate a single-cell resolution transcriptome of the entire fly brain using Drop-seq. In a unique collaborative effort we will mine this data set to uncover molecules that contribute to an array of important neural processes, including: 1. How does Kenyon cell diversity support memory-guided decisions? 2. What is the extent of input specificity to functionally discrete dopaminergic neurons? 3. How do particular peptidergic neurons respond to internal states? 4. How does sex-specific neuronal identity emerge? 5. Is there a rational transcription factor logic for cell-specific gene expression? Our endeavour also possesses significant technological value. Transcriptomic information, and the design of synthetic regulatory sequences that decode cell-specific patterns of gene expression, will improve the precision and resolution with which experimental effector genes can be targeted to pre-determined groups of neurons.

Amount: £3,500,000
Funder: The Wellcome Trust
Recipient: University of Oxford

open access award 2017/18 30 Sep 2018

Not available

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice 24 Apr 2018

The recent Deciphering Developmental Disorders Study found that mutations in genes encoding epigenetics proteins are a primary cause of intellectual disability. These disorders are incurable and their underlying mechanisms remain elusive. Intriguingly, varying symptom severity has been described in patients with the same causative mutations for a number of these disorders and phenotypes displayed in some mouse models are strain-dependent. To search for secondary mutations that suppress phenotypes in mouse models of the neurological disorder, Rett syndrome, Monica Justice’s lab performed a genome-wide screen by inducing random mutations with the chemical mutagen ENU. I aim to take advantage of recent advances in CRISPR/Cas9 technology to develop a CRISPR-based screening method. This method will simplify isolation of modifying mutations, greatly reduce the number of animals required and can be adapted for recessive screening. I will use this method to screen for suppressors of two neurological disorders that are predicted to be modifiable: ATR-X and ADNP syndromes. Both causative genes encode epigenetic proteins: ATRX is a chromatin remodelling ATPase and ADNP is a putative transcription factor. I hope that the ‘hits’ obtained in these screens will help us to better understand ATRX/ADNP protein function and open up therapeutic avenues for patients.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Medicine Quality and Public Health Conference 2018 30 Sep 2018

Globally, medicine regulatory authorities, research groups, international organisations, law enforcement agencies and other key stakeholders, including the pharmaceutical industry, are trying to keep patients safe and ensure that the benefits of modern medicine are delivered to patients. However, organisations working in this field tend to be fragmented with the wide diversity of professionals required to tackle this important issue, from chemists to lawyers, rarely discussing solutions together. Indeed, there has never been an opportunity for the diverse stakeholders involved in medicine quality and drug regulation to come together – within the framework of a specific academic conference – to share ideas and expertise, and to outline the coordinated steps that need to be taken to tackle the problem on an international scale. Drawing on the achievements of our successful, annual, multidisciplinary course on the Quality of Medical Products & Public Health at the London School of Hygiene & Tropical Medicine and Boston University, we are organising the first-ever dedicated academic and programmatic conference on Medicine Quality and Public Health. Wellcome is supporting the attendance of 10 participants from LMICs.

Amount: £24,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement Provision. 20 Apr 2015

It is anticipated that by 2020 there could be considerable advances in genomic medicine. However, even with demonstrated clinical utility it is uncertain whether such advances will have benefits for patients, because research findings are not routinely implemented into clinical care. To facilitate translational research new sets of partnerships and ways of working are needed between patients, clinicians, researchers and commercial partners. Biobanks potentially lie at the heart of these new rela tionships, as they can be used for patient care, but also for different kinds of research. For biobanks to become key nodes in translational research new practices, policies and protocols are needed. This research will carry out a number of interviews and workshops with stakeholders involved in the Oxford Radcliffe Biobank (ORB) to understand the issues at stake. I will also draw on best practice elsewhere in the world, particularly the US and the Netherlands, to help develop practical solutions in this rapidly changing field. This research will provide an evidence base for national policy formulation which could make ORB an exemplar of best practice for clinical biobanks in the UK. Lessons learnt within ORB could be applied elsewhere in the UK and Europe where similar initiatives are underway.

Amount: £171,014
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £58,249
Funder: The Wellcome Trust
Recipient: University of Oxford

Towards an Effective Vaccine against Blood-Stage Plasmodium vivax Malaria. 24 Jun 2015

Growing recognition of the huge morbidity and significant mortality attributable to Plasmodium vivax (P.vivax) malaria has led to renewed calls for an effective vaccine against this most widespread of the human malarias. The leading vaccine candidate antigen has long been the P.vivax Duffy-Binding Protein region II (PvDBP-RII) with which the parasite attaches to the Duffy antigen on the red blood cell membrane and enters the cell. This was put to the test last year in Oxford in the first human vaccine trial against blood-stage vivax malaria in which 24 volunteers were vaccinated with PvDBP_RII. PvDBP-RII does, however, show significant inter-strain polymorphism and this may jeopardise the vaccines' potential to induce strain transcending immunity A new and promising candidate antigen, the RH5-Ripr Membrane-Anchoring Protein (RRMAP), has recently been described. It is also essential for red cell entry and appears to be highly conserved. To assess the potential of these two antigens , I will produce monoclonal antibodies from the serum of the human PvDBP_RII vaccinees and raise rabbit antisera against RRMAP. I will then test and compare these antibodies in novel functional parasite invasion assays, progressing the most promising to detailed structural studies with my Co-Supervisor in the Department of Biochemistry.

Amount: £271,399
Funder: The Wellcome Trust
Recipient: University of Oxford

The evolutionary biology of antibiotic resistance. 01 Apr 2015

Antibiotic resistance poses a growing threat to human health. Natural selection drives the spread and maintenance of antibiotic resistance, but most of our understanding of the evolution of resistance comes from simple in vitro experiments and animal models. My project will bridge the gap between clinical microbiology and evolutionary biology by elucidating the evolutionary processes that drive the spread and maintenance of antibiotic resistance in clinical populations of pathogenic bacteria. Ul timately, this research will contribute to the development of improved methods for mitigating the spread of resistance. Key Objectives: 1. To determine the impact of antibiotic use on bacterial population structure and genetic diversity. 2. To determine if resistance evolves by selection on (i)standing or (ii)novel genetic variation. 3. To estimate the fitness cost of resistance following antibiotic treatment. 4. To determine the rate of compensatory evolution in resistant lineages. 5. T o determine the impact of (i) competition, (ii) immigration and (iii) reversion on the loss of resistance. 6. To determine the genomic basis of resistance evolution. We will study resistance evolution using natural experiments where longitudinal samples of important pathogens (S.aureus and P.aeruginosa) have been obtained from individual patients pre and post exposure to antibiotics. To study evolutionary responses to antibiotics, we will use a combination of whole-genome sequencing and phe notypic assays (resistance, competitive ability, virulence) on individual isolates. In vitro experiments and genetic manipulation will then be used to further investigate the phenotypic and evolutionary consequences of observed changes in the clinical samples.

Amount: £1,336,460
Funder: The Wellcome Trust
Recipient: University of Oxford

Optimising antimalarial combination therapies in an area coendemic for vivax and falciparum malaria 07 Jul 2015

I have established a large network of researchers, service providers, and policy makers in Papua, Indonesia to undertake a series of epidemiological, clinical, and laboratory studies to optimise the treatment and prevention of malaria. Previous studies led to a district-wide (population 180,000) change in policy for uncomplicated malaria to artemisinin combination therapy in 2006. The current proposal will expand our research agenda to address the next phase of ACT deployment, notably an underst anding of the co-factors that determine its impact and cost-effectiveness and how these differentially affect P. falciparum and P. vivax. Novel and complementary studies are planned to optimise the treatment of vivax relapses, improve the diagnosis of G6PD deficiency and develop genetic tools for monitoring drug resistance. This research will provide the evidence base upon which to optimise malaria control programmes. The crucial involvement of collaborative partners in the District Health Au thority, local government and Indonesian National CDC will ensure that the results of the project impact directly on MoH policy decisions not only for Papua but also elsewhere in Indonesia. My objective is that these tools will be endorsed by WHO and adopted by the current global elimination efforts.

Amount: £107,663
Funder: The Wellcome Trust
Recipient: University of Oxford

Senior Research Fellowship in Clinical Science 03 Dec 2014

This proposal will address the questions of whether microparticles of iron oxide can be used asreliable and conspicuous molecular probes for magnetic resonance imaging to (1) detect, inquantitative fashion, the endothelial expression of pro-inflammatory molecules, (2) identify featuresof subclinical disease that predict later disease burden and (3) quantify responses to treatmentthat are invisible to current imaging approaches. Further, we will evaluate, in comparative fashion,the binding characteristics of existing and novel ligands (including synthetic glycoproteins) and wewill establish the characteristics of our new generation of biodegradable iron rich microparticles forimaging.

Amount: £216,553
Funder: The Wellcome Trust
Recipient: University of Oxford