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Recipients:
University of Oxford

Results

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

From molecules to pandemics: multi-level adaptation of human chronic viruses. 27 May 2015

Chronic viruses, such as HIV and HCV, evolve rapidly within individuals. Combined with long durations of infection, this means transmitted strains will be different from founder strain(s) that initiate infections, which in turn will have large effects on these viruses at the epidemiological scale including: the rate of spread of transmitted drug resistance; adaptation to the HLA background of the host population; and the evolution of viral pathogenesis. I will determine how virus evolution withi n-hosts affects the epidemiology of chronic viruses and predict the consequences of these effects under different intervention scenarios. It is becoming increasingly apparent that the presence of viral reservoirs and compartmentalisation has qualitative effects on within-host viral evolution. I will fit mathematical models to next-generation sequencing data to establish whether this significantly delays within-host evolutionary dynamics in natural and drug treated infections, and whether vir al strains similar to founder strains are preferentially transmitted. Importantly, I will test whether we see the same patterns for different classes of mutations, such as immune and drug escape mutations. This will allow me to develop epidemiological models that integrate within-host and transmission processes and ask how this impacts the among-host evolution of chronic viral infections.

Amount: £753,548
Funder: The Wellcome Trust
Recipient: University of Oxford

How chemokine signalling and antigen recognition are integrated by T cells. 13 Apr 2015

Integration of diverse signals at the immunological synapse (IS) is fundamental to T-cell responses. Although its structure is well studied regarding the organisation of proteins directing cell-cell interactions, how signalling by G protein-coupled receptors (GPCRs) in general, and chemokine receptors in particular, is integrated at the IS is surprisingly poorly understood. This proposal aims to characterise spatiotemporal chemokine receptor organisation within the IS using confocal and single-m olecule microscopy of four receptors of particular interest. The mechanisms mediating receptor organisation will be elucidated by reconstructing the antigen-presenting cell surface with artificial bilayers, and using interaction-deficient receptor mutants. I will examine the IS-dependency of signal-integration by visualising signalling events therein in the presence and absence of chemokine gradients, and by perturbing normal IS organisation, complementing imaging with biochemical assays. I will also determine which of the 54 Rhodopsin-family GPCRs expressed natively by T cells participate in cellular activation through systematic knock-outs; comprising the first system-level analysis of T-cell GPCR function. This will provide new insights into the extent to which GPCR function is enhanced at IS-like structures and the importance of these structures for lymphocyte cell-cell communication generally. This research also has the potential to identify new immunologically and/or pharmacologi cally active receptors.

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

It's about time: the role of temporal context in adaptive auditory coding. 19 Nov 2014

Encoding the temporal organization of natural acoustic scenes is essential for accurate comprehension of sounds, but research on the role of temporal structure in adaptive auditory coding is lacking. In this proposal, I will investigate the neural mechanisms that govern how temporal context shapes auditory learning and memory. The first project will assess how temporal structure is learned implicitly by decoding of rapid memory formation from population activity in auditory and frontal cortical regions. We hypothesize that memory formation becomes progressively more evident and robust from primary to non-primary auditory cortical areas, and most explicit in frontal cortex. The second project will study explicit learning of temporal structures associated with differential timing of rewards and examine whether timing of rewards during behaviour is encoded by primary auditory cortex. These questions will be addressed in humans using electroencephalography (EEG), which allows access to ens emble responses across multiple cortical regions. In ferrets, the use of planar microelectrode arrays (up to 96 channels) will provide a broad coverage and yield simultaneous responses across primary and non-primary auditory cortex during behaviour. Taken together, this integrative approach will help identify the neural bases of encoding and learning of the temporal structure of natural sounds.

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

Understanding the cytotoxicity of pyocin L1 as a tool for antibiotic development. 19 Nov 2014

This project aims to identify the molecular target through which the lectin-like bacteriocins (LLBs) exert their cytotoxicity, and define its interaction with pyocin L1 and other homologous LLBs. Pyocin L1, which is active against Pseudomonas aeruginosa, is the best characterised LLB and will be used as the model in this study. The three key aims of this project are: Aim 1. Determine the cellular target and mechanism of P. aeruginosa killing by pyocin L1. Aim 2. Characterise the cell enve lope stress response of P. aeruginosa to pyocin L1. Aim 3. Characterise the pyocin L1-target interaction. Aim 1 will use several complementary techniques to determine the genetic basis of resistance to LLBs, identify interaction partners using co-purification techniques and study the interaction of LLBs with live cells, in real-time. Aim 2 will define the global transcriptional response of P. aeruginosa to pyocin L1 and other antibiotics, generating information on the poorly understood env elope stress regulon in P. aeruginosa. Aim 3 will use X-ray crystallography and biophysical techniques to study, in detail, the interaction of pyocin L1 with its cellular target. The interactions of other LLBs with this target or homologous targets will also be studied.

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

Workshop on the ethical issues in participatory community-led media in engagement with biomedical research. 02 Feb 2015

Participatory community-led media (CLM) has been used within the development sector for well over 30 years but recently we are seeing it used increasingly within engagement with biomedical research programmes in developing country contexts. Despite wide use of participatory CLM the conversation around ethics and the use of these methods is still quite young. Bringing these methods into the context of biomedical research raises further ethical questions. Despite its potential, the use of CLM for social research or engagement raises fundamental ethical questions especially around anonymity and consent and dissemination of the media. Through the workshop we hope to share experiences, develop our theoretical thinking and practical skills relating to these questions. We propose to bring together a group of academics, ethicists and practitioners from Wellcome Trust Major Overseas Programmes to discuss the use of participatory community led media with a focus on digital story telling method s with vulnerable groups. The workshop will be held in Siem Riep Cambodia from 12-13th March 2015. It will be chaired by Dr Mary Chambers and Sian Aggett. A total of 18-20 participants will be invited.

Amount: £9,959
Funder: The Wellcome Trust
Recipient: University of Oxford

Reading and Replicating Bodies: Mimicry in Medicine and Culture, 1790-1914 (an Interdisciplinary workshop). 25 Nov 2014

This one-day workshop will bring together scholars working on the subject of mimicry in the history of medicine. The event will explore how, in nineteenth-century medicine and culture, to know a body was to replicate it. It will ask how medical practices and representations sought to mechanically imitate the body with perfect accuracy, from anatomical models and drawings to prosthetics. How did such replication interact with wider cultural anxieties about the mechanization of the human body? The workshop will also discuss how medicine, and the arts more generally, came to represent human bodies as social-emotional mirrors that instinctively mimicked each other. The meeting will analyse the different, sometimes contradictory, views which emerged of such mimicry, sometimes pathologized as primitive or degenerate, and other times valued as a natural source of sympathy and empathy between humans. The event will trace the afterlife of these practices and concepts in modern bioethical debate s and views of humans as copying animals. The workshop will be held at The Oxford Research Centre in the Humanities (TORCH) and we plan to publish essays based on the event in a guest-edited issue of the open-access online journal 19: Interdisciplinary Studies in the Long Nineteenth Century.

Amount: £1,722
Funder: The Wellcome Trust
Recipient: University of Oxford

Accelerating the development of next generation malaria vaccines through development of innovative trial designs in malaria-endemic areas. 21 Apr 2015

Malaria remains a public health emergency despite a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate the development of a more effective multi-stage vaccine. We will use controlled human malaria infection in semi-immune adults (CHMI) to overcome two critical blocks in vaccine development: a) a comprehensive prioritization of antigens associated with blood-stage immunity for vaccine development and b) an adaption of CHMI to test proof-of-concept for tr ansmission blocking vaccines in vivo. We will comprehensively characterize immunity to malaria using >100 antigens in thousands of semi-immune adults, then select 200 with a range of different immunological profiles, and conduct CHMI studies with serial quantitative PCR to measure the parasite growth rate in vivo and relate this to host immunity. In addition we will vary the parasite dose in CHMI and use low-doses of anti-malarial drugs if necessary to produce gametocytes in vivo and demon strate transmissibility to mosquitoes fed on participants blood. We will use the CHMI studies to test candidate pre-erythrocytic vaccines, blood-stage vaccines and transmission-blocking vaccines.

Amount: £4,876,229
Funder: The Wellcome Trust
Recipient: University of Oxford

A systematic approach to understanding the biology underpinning GWAS hits. 28 Oct 2014

Genome-wide association studies have been extraordinarily successful in identifying DNA sequence variants associated with human diseases and phenotypes, with thousands of risk-loci identified across hundreds of traits. Each of these loci has the potential to reveal novel insights into human biology which can in turn underpin future translational advances. However GWAS loci frequently lie within regulatory sequences which complicates efforts to deliver actionable biological insights. To date, ch aracterisation of the molecular basis of predisposition to specific traits and diseases has been limited to a handful of the many thousands of non-coding GWAS signals. This lack of successful follow-up has impeded the GWAS approach from realising its huge potential. Recently, there have been major advances in our understanding of the regulatory architecture of the human genome, and, in particular, in the development of techniques for assessing the relationships between regulatory elements and t he genes they control. This application seeks funding for international leaders in GWAS, human gene regulation, human disease, and statistical genetics to exploit these recent advances by developing a systematic approach to the functional follow-up of GWAS loci and applying this across a series of diseases selected to represent increasingly complex challenges to biological inference.

Amount: £2,652,112
Funder: The Wellcome Trust
Recipient: University of Oxford

Accelerated Clinical Evaluation of a Monovalent Vectored Ebola vaccine 29 Aug 2014

Conversations between the principal investigator, The Wellcome Trust and various other parties have led to this application being submitted for fast track assessment. The goal is to demonstrate the safety and immunogenicity in UK and West African adults of a vaccine for the Zaire strain of Ebola virus that has shown significant promise in pre-clinical studies conducted at the NIH in collaboration with Okairos, now GSK. Demonstration of the safety and immunogenicity of this vaccine by November 2014 in about 140 subjects would provide WHO with the option of providing this vaccine to affected countries, particularly for use in health care workers, for whom no other intervention is currently available.

Amount: £910,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Strategic Support Fund 2013/14 14 Oct 2013

The ISSF has been renewed for two years (2014-2016) for an additional £3M of funding, and has a remit to: Assist the Institution in developing its research strategy across Departments and Divisions. Encourage new inter-departmental synergies, cross-disciplinary collaborations, and inter-institutional initiatives. Add value to existing Wellcome Trust investments in the Institution. The ISSF is a block grant provided to the University, which is managed by a small central committee. The ISSF Committee receives applications for funding from any department in the University. Research projects must fall within the remit of the Wellcome Trust, as well as the strategic remit of biomedical research at Oxford. The fund was first awarded in 2011-2012 with a £1.5M grant from Wellcome, to be matched by £1.5M from the University. For the first year, 25% of the total cost was met by the central University John Fell Fund (£750K). The fund was renewed for two additional years at £1.5M a year, and has now been renewed for a 2-year period through 2016. ISSF funding requires a 50% or greater matching contribution from the Department or University; the source and amount of matched funding must be stated at the time of application, and will be subject to Wellcome Trust oversight at the point of award.

Amount: £1,500,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The immunobiology of autoantibody-mediated diseases of the central nervous system. 14 May 2014

The last five years have seen a dramatic increase in the number of patients diagnosed with autoantibody-mediated encephalitis. These diseases appear partially immunotherapy-responsive. The two commonest antibody targets are leucine-rich-glioma-inactivated-1 (LGI1) and the NMDA-receptor. LGI1-antibodies respond well to glucocorticoids over several months, whereas NMDAR-antibodies may only fall over several years despite multiple immunotherapies. The time-course of these reductions parallel the ra tes of clinical improvement. These differences are likely to be determined by the relative persistence of different antibody-secreting cell (ASC) populations. However, this hypothesis has not been addressed. First, this fellowship will use multicolour flow-cytometry to identify baseline and longitudinal populations of total, and antigen-specific, memory B-cell and ASC populations in patients with LGI1- and NMDAR-antibodies. This will establish their relative baseline characteristics in viv o, susceptibility to immunotherapies and relationships of these measures to clinical outcomes. Second, these cells will be cultured to determine which populations produce LGI1- and NMDAR-antibodies and, subsequently, which factors modulate antibody production and ASC survival. Finally, the plasma membrane proteomic profiles of the ASCs will be studied to identify surface markers which may be potential ASC-specific drug targets. Results should inform future B-cell therapeutics, trial de sign of autoantibody-mediated illnesses and the biology of multiple antibody-mediated diseases.

Amount: £834,107
Funder: The Wellcome Trust
Recipient: University of Oxford

p(L)ace of change - extension. 10 Feb 2014

In the initail phase (1a) of Place of Change we successfully engaged four diverse communities in creating digital narratives that explore attitudes, perceptions and knowledge of specific health themes: HIV/AIDS, STIs, malaria and zoonotic disease risks. This process had produced 29 digitial stories that provide valuable community insights into these issues. We are seeking extension funding to further develop the phase 1a content into a comprehensive media package that also incorporates newly-generated professional and community-authored content, and which can be used to engage a wider audience of community groups, health workers and reearchers. To ensure the most engaging media tools and in-depth stakeholder engagemnt, we will research and develop the best formats for the media package to suit these different stakeholder groups. This development will also include research into the design of focused "forums" for community, researcher and government stakeholder engagement. The resulting forum series will be facilitated group discussions that give a broader range of community, scientific and government stakeholders the oppurtunity to engage with research and health issues, using the media package as a stimulus for discussion. The extension phase will allow the project to build and expand on the relationships developed on phase 1a, and to add value to the existing community-driven content by connecting it with scientific content and government contributions. The forums in which this media package is then presented will enable deeper engagement and understanding between researched and research communities. Finally, we will develop appropriate tools for reviewing both the processes and impacts of this project, which will allow us to contribute to the academic evidence for public engagement in science.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms of HIV disease limitation and cure revealed in paediatric infection . 08 Jul 2014

Without antiretroviral therapy (ART), disease progression following HIV infection is typically faster in children. However, specific opportunities are presented within paediatric infection to better define critical aspects of HIV infection: cure and pathogenicity. One is at birth: the recent description of cure in the Mississippi child followed ART initiated at 31hrs age. A second opportunity, we believe, is in ART-na ve, HIV-infected children, aged >5yo, maintaining normal CD4 counts despite hi gh HIV levels. This group have key features in common with the rare HIV-infected adults who do not progress despite high viraemia, and with the sooty mangabey, who typically suffering no SIV disease. We hypothesise that a central factor underlying cure potential in HIV-infected newborns, and relative non-pathogenicity in the non-progressing older children, is the same: failure to establish a significant viral reservoir in long-lived, resting central memory CD4 T-cells . The underlying mechanisms are likely to be distinct. In newborns establishment of the reservoir in this compartment is difficult because of the paucity of central memory cells expressing CCR5. If a reservoir is not established at all, immediate ART will achieve sterilising cure. If a very small reservoir is established, ART may reduce it to sufficiently low levels to achieve remission - functional cure. In the older, non-progressing children, we hypothesise mechanisms similar to those describe d in natural simian hosts for SIV that protect against infection of the long-lived central memory CD4 cells. Low infection levels in these cells in sooty mangabeys, as in HIV-infected adult viraemic non-progressors, prevent CD4 depletion that occurs in typical, pathogenic infection. Initiation of ART in these groups may therefore quickly eliminate rapidly turning over effector memory cells as a source of virus, leaving a small central memory reservoir to reduce towards remission. The purpose o f this 5-year project is to test these hypotheses. Specifically, we will study samples from HIV-infected newborns and from non-progressing HIV-infected children to determine whether in these groups the HIV reservoir is principally located outside of resting central memory CD4 T-cells. This would provide a strong rationale for ART initiation in such patients to determine whether HIV cure can be achieved. We have already initiated pilot studies in infected newborns to determine the impact of early ART. We here propose extending these to enrol 100 infected infants and initiate ART within 24-48hrs of birth, to determine the likelihood of cure in this setting and its potential mechanisms. Over two decades we have established productive collaborations in South Africa, the country with more HIV infections than any other. We believe we are uniquely placed to access the paediatric study cohorts that make this proposal feasible. Within two specific aims, our research questions include: 1. What is the impact of immediate ART in newborns? Is cure in HIV-infected newborns related to protection from infection of central memory CD4+ T-cells (TCM)? Is CD4 count and/or viral load at birth predictive of cure following immediate ART? What is the impact of ART initiated late

Amount: £2,901,228
Funder: The Wellcome Trust
Recipient: University of Oxford

Bacterial immune evasion. 03 Dec 2013

Not available

Amount: £2,390,550
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access award 2014/15. 15 Sep 2014

Not available

Amount: £75,000
Funder: The Wellcome Trust
Recipient: University of Oxford

A Structure-Function Map of the Interactions of the σ1 Receptor 15 Sep 2014

We aim to generate a protein interaction map for the sigma1 signalling pathway and use this to target biophysical and structural studies. To achieve this aim we will use a concerted in vivo and in vitro approach. Lifetime imaging fluorescence microscopy will be used to monitor interactions by FRETin vivo, with NMR and other structural and biophysical techniques being used to characterise these interactions in vitro. Information from the in vitro analyses will allow for further in cell experiments testing the molecular mechanisms of action of the sigma1 pathway. Initial work with the sigma1– BiP (Binding immunoglobulin Protein) interaction should serve as a test case allowing for the development of methodologies that can be applied to other sigma1 interactions. In the first instance we will expand this approach to the shaker related voltage gated potassium channel family. Starting with Kv 1.4 and Kv 1.5 a fragment based screening approach will be applied to search for points of interaction and look at how sigma1 interacts with and regulates ion channels. This project should not only yield structural information on the sigma1 receptor and its interactions but will also provide a methodological frame work for a systematic dissection of the sigma1 pathway.

Amount: £161,117
Funder: The Wellcome Trust
Recipient: University of Oxford