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Recipients:
University of Oxford

Results

The Role of the Adaptor Protein-2 Sigma Subunit (AP2σ) in Calcium Homeostasis 30 Sep 2016

G-protein coupled receptors (GPCRs) facilitate cellular responses to extracellular stimuli, and GPCR mutations result in many diseases, including endocrine disorders. Mutations of the calcium-sensing receptor (CaSR), a pivotal GPCR in calcium homeostasis, resulting in loss-of-function or gain-of-function cause familial hypocalciuric hypercalcaemia type-1 (FHH1) and autosomal dominant hypocalcaemia type-1 (ADH1), respectively. FHH and ADH are genetically heterogeneous, and loss-of-function or gain-of-function mutations of the G-protein-alpha11 utilised by CaSR, cause FHH2 and ADH2, respectively; while loss-of-function mutations of adaptor protein-2 sigma subunit (AP2sigma), which is critical for clathrin-mediated endocytosis, cause FHH3. To date, the reported AP2sigma mutations, which cause only FHH3 but not ADH, all affect residue Arg15 and impair CaSR signalling and trafficking. However, the Thakker group have recently identified seven other AP2sigma variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu120Gly), and my goal is to determine the roles of these AP2sigma variants in calcium homeostasis by: 1) Characterising their structural-functional relationships by in vitro studies that assess effects on three-dimensional models and on CaSR signalling and trafficking pathways. 2) Determining in vivo phenotypes of AP2sigma mutations by generating knock-in mouse models, using CRISPR-Cas. 3) Assessing pharmacological effects of drugs, e.g. velcalcetide, using above AP2sigma in vitro and in vivo models.

Amount: £348,449
Funder: The Wellcome Trust
Recipient: University of Oxford

Advancing cognitive therapy for anxiety disorders and PTSD 05 Apr 2016

The proposed research addresses two of the major problems in psychotherapy research: How can effective psychological treatments be made available to the large number of people with mental health problems? and How can researchers make rapid progress in making the treatments even more effective? The applicants have developed leading psychological therapies for three anxiety-related disorders (social anxiety disorder, posttraumatic stress disorder and panic disorder). They now propose to harness the power of the internet to solve both problems. Internet-delivered versions of the treatments will be developed and evaluated that require much less therapist time and can be delivered anywhere. Dissemination and evaluation of the treatments within NHS Improving Access to Psychological Therapies (IAPT) services will create a large database that will enable rigorous study of moderators and mediators of therapeutic change to identify targets for further improvements. Modifications of the treatment will then be evaluated in experimental treatment studies. The work will help realise the population level mental health benefits of previous Trust investment in psychological therapy research and align with the Trust’s new focus on maximizing the application of research to improve health by focusing on new product development and the uptake of patient-oriented research advances.

Amount: £3,266,571
Funder: The Wellcome Trust
Recipient: University of Oxford

The demand for prevention in middle and later life 18 Jul 2016

Population ageing is likely to increase the burden of non-communicable diseases (e.g. cancer). Prevention (including health behaviour and screening programmes) can considerably reduce the morbidity and mortality risks of these diseases, and will therefore play a key role in maintaining the health of an ageing population. The research project will investigate the demand for prevention among middle-aged and older people theoretically and empirically. In the first part of the project, I will derive a theoretical framework based on the health capital model that allows me to derive hypotheses on determinants of the demand for prevention, in particular with respect to time costs. In the empirical part of the project I will test these hypotheses using econometric methods for causal inference and data from the UK as well as international data. I will analyse three specific factors that are associated with different levels of time costs and play a major role among older people – retirement, informal care provision and voluntary work. The projected output will consist of at least four academic papers and a number of conference presentations. I will engage members of the public in an advisory group. Keywords: prevention, screening, health behaviour, causal inference, ageing

Amount: £176,150
Funder: The Wellcome Trust
Recipient: University of Oxford

Peripheral blood, Liver and Intestine-specific lymphocytes in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease 19 Nov 2015

The focus of my project is on the relationship between the bowel and the liver in Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD). This is based on the fact that there is a high rate of IBD in patients with PSC, and it has previously been identified that there is an aberrant population of CCR9+ alpha4beta+ gut-homing T-cells in the PSC liver. Additionally, GWAS and Immunochip™ studies suggest an immune-mediated pathway in the pathogenesis of PSC. I propose to investigate a novel immunologic pathway that could be highly relevant to the development of gut inflammation and the link between gut and liver inflammation. I will examine the CD4+ lymphocyte subset, namely, those expressing CD161 and/or CCR9. I have identified that there is an enrichment of CD161++ CCR9+ CD4+ T-cells in the bowel of patients with PSC and I will be analysing the frequency, phenotype, function, and transcription of these cells in healthy patients, and patients with PSC, IBD, and other liver diseases. I will be examining this lymphocyte subset not only in peripheral blood, but also in liver and intestine. Understanding more about this lymphocyte subset may potentially identify a therapeutic target for this difficult to treat disease.

Amount: £265,503
Funder: The Wellcome Trust
Recipient: University of Oxford

Determining how distinct vertebrate promoter classes coordinate cis-regulatory input. 11 Nov 2015

Highly coordinated gene regulation is essential for multicellular development and when perturbed can lead to disease. Normal transcriptional regulation relies on communication between gene promoters and distal regulatory elements (DREs)[9,10], a process that appears to involve extensive interactions between these sites[11-13]. However, the mechanisms driving these interactions remain poorly understood, limiting our capacity to fully understand gene regulation. In order to bridge this major conce ptual gap, I will use cutting-edge genomic and evolutionary approaches to determine how promoters engage with their respective DREs. This will be achieved by focussing on the two major vertebrate promoter types, CpG-rich and CpG-poor, and detailing promoter/DRE interactions in mouse embryonic stem cells. I will then genetically perturb CpG-rich promoter chromatin to determine how chromatin architecture contributes to the establishment of these interactions. Building on this work, I will identify promoter/DRE contacts in related yet divergent vertebrate species to understand how interactions form and are affected by genomic arrangements during evolution. This ground-breaking study will provide novel insight into how promoter type, chromatin architecture and genomic organisation contribute to promoter/DRE interactions, significantly advancing our understanding of gene regulation.

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

Fakes, fabrications and counterfeits: interrogating the social, political and ethical features of pseudo-Global Health 31 Aug 2016

For many decades STS scholars have examined the boundaries between science and pseudo-science, quackery and authentic scientific methodology. These examinations of so-called pseudo-scientific practices, concepts and methods have yielded great insight into the porous divide between what counts as seemingly authentic and inauthentic science. Drawing on concepts and methods developed within STS, this symposium seeks to interrogate areas considered pseudo-global health, namely practices and methods that are deemed inauthentic. Ideas of pseudo-global health have dominated the discourse in the growing markets of counterfeit drugs, equipment and vaccines, to data fabrications and fakes. Such activities are often regarded as undermining ‘real’ global health initiatives and goals. These discussions are premised on ideas that ‘real’, ‘unreal’, ‘authentic’ and ‘inauthentic’ global health is clearly recognisable and moreover, that all global health actors value the same thing(s) – namely that a particular view of authenticity or realness overrides all other concerns. This meeting seeks to address the absence of methodological and theoretical attention given to exploring the social, political and ethical value in pseudo-global health activities. We seek to interrogate the binary positions between ‘real’, ‘pseudo’, ‘authentic’ and ‘inauthentic,’ and elucidate what is often buried in these concepts: the people, processes and agendas.

Amount: £6,292
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural insights into the link between GATA2 and acute myeloid leukemia (AML). 01 Apr 2016

Acute myeloid leukaemia (AML) is a blood-related disease characterised by the uncontrolled proliferation of haematopoietic stem cells lacking the ability to commit to normal differentiation. It is highly malignant, with only a 25% survival rate 5 years after diagnosis, despite intensive therapeutic treatments. GATA2 is a zinc-finger (ZnF) transcription factor broadly expressed in haematopoietic stem cells (HSCs). GATA2 is necessary for maintenance of a regenerative HSC pool as well as lineage-restricted differentiation. Given this, it is perhaps unsurprising that GATA2 mutations have been linked with AML. Currently, little is known about the mechanism of GATA2 function in leukaemias. GATA2 contains 2 ZnF domains (NF and CF), which have been shown to bind different DNA motifs and protein partners in vivo. I postulate that these interactions are necessary for the biologial activity of GATA2, and will attempt to show that mutations in the NF and CF domains result in loss of this activity. This will be achieved by using a combination of methods including bioinformatics, molecular docking and in vitro biophysical studies using generated GATA2 mutants. This research aims to show that GATA2 mutants deregulate HSC proliferation by virtue of altering its ability to interact with cognate partners.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Laser capture microdissection to investigate bacterial handling defects in patients with monogenic inflammatory bowel disease 01 Apr 2016

Inflammatory bowel disease (IBD) is linked to defective bacterial handling in Crohn’s disease and monogenic diseases (Hugot et al. Nature 2001, Ogura et al. Nature 2002, Cooney et al. Nature Medicine 2010, Uhlig Gut 2013 and Uhlig et al. Gastroenterology 2014). Hypothesis: If defects in clearance of ingested bacteria cause granuloma formation we expect to find surviving bacteria (and its mRNA) in the granuloma lesions. Experimental Design Formalin-fixed archived tissue sections from patients with monogenic forms of IBD (XIAP , G6PC3 or HPS1) will be cut onto a capture membrane and stained with H&E. Granuloma will be isolated using laser capture micro dissection. 16S rRNA will be amplified using high fidelity PCR and sequenced. Comparison of the obtained sequences with public databases will establish which bacterial taxa. This project will help to identify bacteria that survive within macrophages and improve the understanding of the host-environment relationship.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Viet Nam Major Overseas Programme core grant renewal 2015-2020. 21 Apr 2015

Our vision for the Viet Nam Major Overseas Programme is to perform world-leading clinical research with a major impact on local and global health. We will lead a research-driven response to the major and rapidly evolving challenges to healthcare in Asia. We will build regional scientific capacity through a unique and synergistic network of research units, led by the Oxford University Clinical Research unit in Ho Chi Minh City and Hanoi, Viet Nam, and incorporating the Eijkman-Oxford research unit in Jakarta, Indonesia, and the Patan-Oxford research unit in Kathmandu, Nepal. After a decade of development and research diversification, the programme will place emphasis on increasing the impact of our science, the quality of our research, and the efficiency of our operations. Our core research themes will make defining contributions to the understanding of infectious diseases transmission and susceptibility; will develop new tools to prevent, control and treat antimicrobial resistant organisms; will improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and will enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to remain ambitious and to deliver world-class research across these themes.

Amount: £11,890,784
Funder: The Wellcome Trust
Recipient: University of Oxford

Viet Nam Major Overseas Programme core grant renewal 2015-2020. 21 Apr 2015

Our vision for the Viet Nam Major Overseas Programme is to perform world-leading clinical research with a major impact on local and global health. We will lead a research-driven response to the major and rapidly evolving challenges to healthcare in Asia. We will build regional scientific capacity through a unique and synergistic network of research units, led by the Oxford University Clinical Research unit in Ho Chi Minh City and Hanoi, Viet Nam, and incorporating the Eijkman-Oxford research unit in Jakarta, Indonesia, and the Patan-Oxford research unit in Kathmandu, Nepal. After a decade of development and research diversification, the programme will place emphasis on increasing the impact of our science, the quality of our research, and the efficiency of our operations. Our core research themes will make defining contributions to the understanding of infectious diseases transmission and susceptibility; will develop new tools to prevent, control and treat antimicrobial resistant organisms; will improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and will enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to remain ambitious and to deliver world-class research across these themes.

Amount: £16,671,343
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford part of Kenya MOP renewal 2010 - 2015. Transfer to Philip Bejon. 22 Jun 2015

This proposal is for core funding for an integrated programme of health research conducted in East Africa through the KEMRI Wellcome programme. Core funding supports the essential infrastructure and personnel to provide a platform on which the specific research components, are built. The research programme it self is embedded in a national research institute (KEMRI) but has collaborative links to a large number of governmental, educational and research institutions in Kenya and the East A frican region . The research programme is conducted by 32 principal investigators, funded by competitive research grants and fellowships, working closely together under four main disciplines: (1) Clinical Sciences (2) Epidemiology, Demography and Public Health (3) Pathogen Biology (4) Health Systems and Social Science Research. For the period 2011-2016 the programme has four key strategic scientific themes: Improving child survival during a period of rapid epidemiological transition Ad dressing adult health focussing on maternal health and recognising the impact of HIV on vulnerable populations Strengthening health systems through research on policy for, access to, monitoring, evaluation and delivery of care. Applying basic science to develop new interventions to realise the enormous potential of new technologies in the post genomic era.

Amount: £16,433,919
Funder: The Wellcome Trust
Recipient: University of Oxford

Viet Nam Major Overseas Programme Core Grant Renewal 2010-2015 supplement: Patan Hospital emergency equipment 29 May 2015

Infectious diseases remain a very real global threat. In addition to the endemic infections there has been emergence of new, often zoonotic, diseases and the rise of drug resistance among all major pathogens. Asia is the epicentre of these changes. Within a four hour flight of Vietnam live half the world s human population and 75% of the world s poultry. The region is a global hot spot for the emergence of new infectious diseases, it leads the world in drug resistance, and is going through an unprecedented period of social and environmental change. The future impact of these changes is difficult to predict but it will influence disease patterns both directly and indirectly. We believe that this trusted collaboration between Vietnam and the Wellcome Trust is uniquely placed to address these complex issues both nationally and regionally. Our work keeps health research as the focus with an integrated science programme and a particular interest in the interface between human and animal health. Our training and public engagement programme from schools to post-docs and lay people is helping to build a critical mass of Asian clinicians and scientists dedicated to the development of the region and the health of its people.

Amount: £97,609
Funder: The Wellcome Trust
Recipient: University of Oxford

A spatial data repository for the analysis of insecticide resistance in malaria vectors. 11 Jun 2015

We will build a resource to provide georeferenced data on resistance to multiple classes of insecticide in vectors of malaria worldwide. Our key objectives are i) to collate the largest global repository of field survey data for insecticide susceptibility, ii) to generate predicted values for insecticide susceptibility across locations and times to provide estimates for locations that have no field survey data and to allow users to investigate the spatiotemporal patterns of resistance, and iii) to collate the largest global repository of field survey data for resistance mechanisms. Cutting across all three objectives, our aim is to provide datasets that are formatted for use in mathematical models of malaria transmission and meta-analyses of insecticide resistance. The survey data will be cleaned, standardised, disaggregated and georeferenced before they enter the repository, to ensure users can conduct meta-analyses on data from diverse sources and study designs. We will use geostatis tical techniques to generate posterior distributions of predicted values that can be used by mathematical modellers and we will also provide a mean estimate for each location and time, together with a summary statistic for the uncertainty in each estimate. All data will be released on a free and open access basis.

Amount: £669,719
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

Animal Ethics. 27 Oct 2014

Professor Christine Korsgaard (Arthur Kingsley Porter Professor of Philosophy, Harvard University)will visit Oxford December 1 -3 for a series of 3 lectures, The Moral and Legal Standing of Animals , where she will also seek to discuss our resulting moral obligations towards them. This event capitalises on her presence to bring together a group of philosophers, ethicists, lawyers, veterinarians, and those working in research ethics policy and ethics management to discuss the moral and legal sta nding of non- human animals as it relates to practice, particularly in medical research and research ethics. Participants will attend the lectures, and on the third day will convene to give short prepared responses to Korsgaard's lectures, followed by open discussion facilitated by Jeff McMahan. Christine Korsgaard will give a brief response to the commentators. The second part of the event will consist of discussions around any practical implications for research ethics practice. A series of practical recommendations will be drawn up and made publicly accessible on the Uehiro Centre website. This will accompany the podcast and blog on Korsgaard's lectures.

Amount: £3,950
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

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