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University of Oxford

Results

Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors 10 Apr 2018

We have recently projected that the human bHLH-PAS proteins form a class of transcription factors with great therapeutic promise, and propose to subject this family to in-depth chemical and functional explorations. The sixteen members of this family are functionally non-redundant and have genetic links to cancers, metabolic syndromes, inflammatory diseases, and psychiatric conditions. They share common architectural features that include a conserved DNA-binding domain and dual PAS domains. Our specific aims are: 1. Identify chemical ligands for members of the human bHLH-PAS family. 2. Determine the ligand-dependent genomic signatures and cellular pathways governed by family members. 3. Probe the mechanisms by which chemical ligands manifest their activities through this family. These studies allow us to transition from having visualized their ligand binding properties to employing chemical tools for interrogating and manipulating their functional activities as transcription factors.

Amount: £400,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Rational decisions: the ethics of rationing in newborn intensive care. 14 Jan 2015

My aims are to: 1. Draw on my unique combination of clinical experience and philosophical training to rigorously analyse ethical questions involved in resource allocation in NICU 2. Develop recommendations on: a. Whether or how cost-effectiveness should be applied to life-sustaining treatment in NICU b. The development of thresholds for intensive care on the basis of resources c. Whether disability may be factored in to resource allocation decisions (compared with other factors such as ch ance or duration of survival) d. How resource allocation in NICU should compare with other settings (for example adults, developing countries) 3. Publish my findings in a series of 9 papers in leading medical and bioethics journals 4. Organise a conference in Oxford bringing together clinicians and ethicists to debate resource allocation for NICU; Edit a special issue of the Journal of Medical Ethics based on the conference 5. Publish a monograph on the ethics of resource allocation in NICU 6. Communicate my findings with clinicians, policy makers, politicians and the wider public through involvement in national policy development, public lectures, feature articles, editorials, media interviews, 7. Establish myself as a clinical academic and expert in NICU and medical ethics

Amount: £248,203
Funder: The Wellcome Trust
Recipient: University of Oxford

Childhood Maltreatment and Lifetime Resilience: an archival pilot study. 20 Jul 2015

Childhood maltreatment and lifetime resilience is a new research project that seeks to understand the lives of people who experienced maltreatment during childhoods in Britain c.1930-1975. The project is innovatively interdisciplinary and collaborative, combining historical and psychological approaches to study how, and to what extent, people navigated pathways to resilience across their lives. Existing studies of resilience in the face of maltreatment have focused on protective factors in child hood, so that little is known about pathways to resilience over the life-course and how historically-specific understandings of maltreatment affect these. This research begins to fill these gaps in academic scholarship, so as to also contribute to improvements in policy-making and practice. Our application relates to the first stage of this research, in order to conduct a small pilot study using the archives of The Children's Society. The relevant case files relating to children who grew up i n charitable care following identified maltreatment are uncatalogued and have not been subject to previous academic study. It is therefore necessary to conduct an initial systematic examination of these files, so as to plan future research with the knowledge of possibilities and challenges these sources pose for qualitative and quantitative analysis.

Amount: £4,437
Funder: The Wellcome Trust
Recipient: University of Oxford

Digitisation of the Journal of the Royal Naval Medical Service archive, 1915-present. 25 Nov 2014

To preserve and provide access to, the archive of 14,349 pages of the Journal of the Royal Naval Medical Service by digitisation.

Amount: £2,230
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of the nuclear exosome complex in RNA regulation. 01 Apr 2015

Accurate regulation of RNA levels in eukaryotes is integral to many aspects of cellular metabolism including establishment of cell identity and survival. A conserved multisubunit exosome complex of 3'-5' exo- and endonucleases is absolutely essential for maintaining the proper levels of functional RNA and specific elimination of defective RNA in both nucleus and cytoplasm. However, the mechanisms providing specificity to the nuclear exosome complex in targeting specific classes of RNAs are poorl y understood, in contrast to the well-studied regulation of cytoplasmic decay. Understanding of the normal exosome function is of major biomedical importance, as deregulation of the exosome activity is associated with several severe human diseases. We recently discovered several RNA-binding proteins that function by directing the exosome complex to the specific RNA targets in the nucleus. Our aim is to advance the field further by uncovering mechanistically how these factors (exosome regulating factors, ERFs) regulate exosome activity. In the longer term, these new insights will be crucial for our understanding of the key molecular events that mediate cross-talk between transcription, RNA-processing and surveillance machineries to control the fate and function of RNA. Together, these studies will be instrumental to advance our understanding of how accuracy and efficiency of gene expression is achieved in health and disease.

Amount: £1,721,292
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

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

Exploring how the germinal center cellular program promotes efficient affinity maturation 29 Oct 2014

High affinity antibodies develop in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for limiting T cell help; affinity-promoting mutations allow cells to acquire more antigen and present greater amounts of peptide-MHCII. How GC B cells deal with the unique demand of rapidly and repeatedly switching BCR specificity while ensuring selection occurs only on the basis only their newest specificity is not known and will be a major focus of this fellowship. We will generate new genetic tools to allow us to temporally tag and fate-map receptors and MHCII proteins, thereby addressing how and when old molecules are replaced. We will test the hypothesis that antigen-presentation is favored at particular cellular stages, and peptide-MHC complexes degraded at others. The molecular mechanisms controlling this will be examined. GC B cell behavior is determined in large part by an intrinsic cellular program that involves a ti mer component to govern switching between states - we will begin a longer-term quest of understanding how this is regulated by probing changes that occur within individual cells as they transition through the program. This work will help elucidate how quality antibodies are generated during infections and after immunizations.

Amount: £1,282,162
Funder: The Wellcome Trust
Recipient: University of Oxford

Specific Neural Circuits and Neuromodulation Underlying Real-Time Cost-Benefit Decision-Making. 13 Apr 2015

-Project aims to discern what temporally-precise cost-benefit (e.g. reward-rate/vigour-cost/fatigue) computations specific dopaminergic/serotonergic neurons perform within neural-circuits, to modulate not just which actions to choose, but also *when* and *how fast*. -I will leverage our understanding of dopamine to understand serotonin's computational-role. -Hypotheses tested: tonic dopamine/serotonin computes reward-values/reward-rates/vigour-costs whilst phasic dopamine computes reward-predi ction-errors mediating task-re-engagement. These are confounded in previous work which (a) studies choices between actions, ignoring their durations/time-courses, (b) cannot specifically-identify/manipulate neuron-types. -Using behavioural-invigoration (when, how fast to perform actions) as an instantiation of real-time cost-benefit decision-making, I will: use normative, real-time Reinforcement-Learning theoretical approaches (which I developed during my PhD) to specify *temporally-precise c ost-benefit computations* and predict the microstructure of behaviour. test predictions by assessing *real-time behaviour* (latencies of every response and re-initiation) using well-controlled vigour-task (fixed-ratio schedule). electrophysiologically record from optogenetically-identified dopamine/serotonin neurons to establish *what temporally-precise costs/benefits* these implement through phasic/tonic firing. optogenetically activate/inhibit these neurons at specific moments-in-time to establish their *sufficiency* and *necessity* for real-time cost-benefit behaviour. measure sub-second dopamine release in downstream striatal targets, using fast-scan cyclic-voltammetry, to establish *communication of computations*. quantitatively fit data and tease apart behaviourally indistinguishable computations using Reinforcement-Learning and Bayesian data-analysis techniques.

Amount: £250,000
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

Medicine of Words: Literature, Medicine, and Theology in the Middle Ages. . 02 Feb 2015

Funding is requested to host a conference, Medicine of Words: Literature, Theology, and Medicine in the Middle Ages planned to take place at St Anne's College, Oxford, on 11-12th September 2015. The conference will mark the final year of the project, Salus Animae: Therapeutic Reading in Medieval England funded by the Leverhulme Trust (October 2012 September 2015) and hosted by the Faculty of English Language and Literature. This project explores how reading was understood as a therapeutic act d uring the Middle Ages. Specifically, it investigates how vernacular religious writings directed at the laity aimed to promote health of the soul by evoking intense negative emotions such as fear and sorrow. The conference aims to disseminate the research undertaken by the project: the medieval understanding of therapeutic reading, the impact of theology on therapeutic reading, and how monastic reading practices were developed for wider use by the laity. The conference also aims to disseminate re search by scholars working in related areas in the UK, the European Union, and USA; to highlight the potential of this field for graduate research; and to initiate new collaborations in order to continue and build on the research pioneered by the project.

Amount: £5,657
Funder: The Wellcome Trust
Recipient: University of Oxford

Application for student and developing country bursaries to attend the HeLEX Oxford & ELSI 2.0 Conference 'Exploring ELSI aspects of translation in healthcare', University of Oxford, June 2015. 27 Oct 2014

This HeLEX five year celebration and inaugural ELSI 2.0 conference will be held in Oxford on the 23rd, 24th and 25th of June 2015 and will explore the broad theme of Translation in Healthcare. It will be an interactive event allowing people from a wide range of disciplines to contribute to discussion and engage with these issues. Often the best connections and most exciting ideas begin in the coffee break; we want to capture this quality and apply it to the whole conference. HeLEX and ELSI 2.0 w ant to build on ELSI work to date by looking outward to make connections and invite wider perspectives on the global ELSI agenda, especially from hitherto under-represented parts of the world. In part this will involve much greater use of networking and collaboration technologies but this also involves invitation of as many researchers and students from around the world as possible to attend this conference and become involved in ELSI 2.0 from the outset. For this reason we are particularly see king funding for bursaries for students and attendees from low resource countries to attend the conference which will then be open for applications on our website.

Amount: £4,990
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

The use of the internet to train clinicians to implement psychological treatments. 20 Apr 2015

Empirically-supported psychological treatments have been developed for a range of psychiatric disorders. If patients are to benefit from these treatments there is a need to develop effective and efficient means of training clinicians to deliver them. A programme of education research is proposed. The primary aim of this research is to evaluate the use of the internet to help clinicians acquire the knowledge and skills required to implement psychological treatments. Two uses of the intern et will be studied. The first (internet-enhanced training) involves trainees being provided with access to a specially designed clinically-rich website which provides extensive information on the psychological treatment together with multiple acted illustrations of its key procedures. Access to the website is followed by an enhanced form of case supervision that makes extensive reference to the website. The second form of training involves access to the website alone with no case supervision ( internet-only training ). This form of training has the potential to be highly disseminable. The effectiveness and cost-effectiveness of these two new forms of training will be compared with that of conventional training (a two-day training workshop followed by case supervision) in a randomised controlled education trial that will employ new measures of clinical competence.

Amount: £150,000
Funder: The Wellcome Trust
Recipient: University of Oxford

New genetic, imaging and microfluidics technologies for single cell genomics 11 Jun 2015

Two major limitations of single cell genomics is (i) the loss of information about the original location within the sample of the sequenced cell and (ii) low throughput at high cost with only hundreds of cells analysed per day. Miniaturising single cell analysis to pico-litre volumes will critically facilitate higher throughput (10^4 - 10^6cells) at lower costs and sidesteps restrictions in handling. Combined with genetic technologies to record lineage history and spatially localise cells this w ill allow questions to be address at single cell resolution that are essential to understand cell diversification following tissue-contextual interactions and the impact it has on gene transcription. 1) We will develop microfluidics based devices to increase sequencing throughput by increasing the number of cells processed at a low cost, and at the same time enabling the complex handling and manipulation of small cell numbers with minimal loss. 2) We will develop genetic technology to: i) record within the genome the lineage history of each cell, for readout at any stage of interest and ii) to provide a unique fluorescent signature to cells to enable us to provide spatial and temporal context to their transcriptional profiles.

Amount: £720,708
Funder: The Wellcome Trust
Recipient: University of Oxford

8 month costed extension 20 Jul 2015

The Wellcome Trust Centre for Human Genetics was established in 1994 to undertake research into the genetic basis of common diseases. The objective of the Centre is to gain insight into mechanisms controlling genetic susceptibility to human disease, including the localization and identification of disease genes or disease-causing variants, functional characterization of genetic variants responsible for susceptibility, understanding how they contribute to disease risk in populations and how genet ic factors contribute biologically to disease processes, and the development and application of new analytical tools. In order to achieve this objective the Centre has brought together multidisciplinary research groups collaborating on human and rodent genetics, genetic epidemiology and statistical genetics, functional analysis of disease genes, and structural biology. The Centre has a strong focus of expertise, equipment, and resources centralized in Core groups allowing all research groups to benefit and expand their research strategies. Recent years have seen major advances in human genetics, in which Centre scientists have played leading roles, and we see major opportunities and challenges ahead. This application is for the renewal of the 5-year core award to fund the Centre's Core Groups: Genomics, Bioinformatics, Molecular Cytogenetics and Microscopy, Transgenics, and IT, for the period 1.4.2011 to 31.3.2016.

Amount: £1,466,666
Funder: The Wellcome Trust
Recipient: University of Oxford

PURAK: Wearable Devices for Distal Arm Functionality Rehabilitation 04 Dec 2013

The loss of an arm and hand through amputation following an accident has a drastic effect on the victim. If the victim is also the main wage earner in a family, as is frequent in India, the impact on dependents can be even greater. Providing the victim with a prosthetic hand and rehabilitation at an early stage can boost their chances of regaining ability with their arm and returning to productive work. However prostheses are either not affordable for the large majority of the Indian population or unsuitable for sustainable use and maintenance. The Indian Institute of Science, Bangalore (IISc) has made a breakthrough with new concepts for the design of affordable prostheses. An international collaboration has been formed between the IISc and the University of Oxford with the aim of developing these designs and readying them for commercial manufacture. The IISc, with its expertise in affordable and appropriate design, will work together with biomechanics and clinical trials experts at the University of Oxford and with experts in commercialisation at both centres. This international partnership will ensure the new design ideas from IISc have a major impact on affordable healthcare in India.

Amount: £441,709
Funder: The Wellcome Trust
Recipient: University of Oxford

Enhancement of Strategic Award (091911) entitled: Advanced Microscopy for Chromosome and RNA dynamics 03 Feb 2014

We are requesting a strategic award to establish a new Wellcome Trust Centre for Chromosome and RNA dynamics that will bring together 15 leading investigators from three different Departments within the South Parks Road science campus at the University of Oxford. Our central premise is that by applying and developing advanced in vivo imaging approaches together with novel and innovative methods to track, manipulate and modify defined factors, we can achieve a new level of understanding of the me chanisms that govern the function of complex molecular machines in chromosome and RNA biology, including in the context of developing multicellular organisms. The Centre will provide the essential infrastructure for advanced imaging instrumentation, proteomics, genomics and data storage/curation as well as staff to manage facilities and analyse high volumes of data that are required to achieve our goals. It will also facilitate programs and activities through which we can build a highly interac tive and collaborative interdisciplinary environment. The Centre will significantly enhance the world leading research programmes of participating groups, and through training, mentoring and dissemination activities strengthen this key strategic area within the UK research community.

Amount: £180,225
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating and validating MRI-based markers of white matter microstructure. 02 Dec 2013

Magnetic resonance imaging (MRI) offers remarkably flexible contrast (ability to discriminate between tissues) because it probes water, which exists in almost every tissue environment and is sensitive to local tissue structure. Taking advantage of the flexible contrast in MRI and prevalence of water in the brain, researchers have begun to propose techniques for measuring white matter microstructural properties such as myelination, iron content, axonal diameter and axonal density. The ultimate goal is to create a suite of MRI in vivo histology tools; however, these emergent methods remain at an early stage. I will develop novel measures of white matter microstructure in living humans: specifically, new approaches to susceptibility (Aim 1) and diffusion imaging (Aim 2). The first aim will explore recent advances in image contrast that are based on the tissue property of magnetic susceptibility. I will use Oxford s upcoming state-of-the-art 7-Tesla scanner and a method I recently deve loped to understand and exploit this contrast, which detects chemical species such as iron and myelin. The second aim will consider diffusion methods for measuring the geometric properties of white matter fibers, such as axonal diameter and density. I will develop novel acquisition techniques that are appropriate for use in living humans.

Amount: £161,955
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