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Results

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £10,000
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

Emergency Evaluation of Treatments for Ebola Virus Disease. RAPIDE 12 Sep 2014

We aim to establish a clinical trials platform in two or more Ebola Virus Disease (EVD) treatment centres in West Africa through which the efficacy and safety of un-registered therapeutic products can be rapidly assessed in patients with EVD. Therapeutic options will be evaluated in a standardised format that is consistent with ethical standards and the delivery of patient care in challenging conditions, and will provide data for potential regulatory approval. Following a run-in' observational stage, the initial pragmatic intervention study design is an openlabel, non-randomised trial with sequential enrolment and analysis of subjects and with historic and contemporaneous controls. Multiple products will be assessed separately using a standardised methodology. The trial is designed to distinguish as rapidly as possible between three situations: (a) the treatment is very effective, (b) the treatment is promising and (c) the treatment is ineffective. The platform will be established and operationalized in the near term using two agents studied in series or parallel (depending on availability). The selection of the initial agent for evaluation will be decided within the next two weeks, as additional data become available. The medium term objective is to provide a platform for the evaluation of three therapeutic classes with different modes of antiviral action: neutralising antibodies (e.g. ZMapp, convalescent plasma); RNA inhibitor molecules (e.g. TKM-100802/AVI-7537); other antivirals (e.g. Brincidofovir).

Amount: £3,214,047
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

The role of myelin in experience-dependent white matter plasticity. 02 Dec 2013

The adult brain shows dynamic structural changes with learning and with recovery from damage. Studies in animals are able to characterise such changes with exquisite detail. The vast majority of these studies have focussed on changes occurring in grey matter. We recently provided evidence for learning-related change in the microstructure of white matter pathways of the adult human brain. However, the measures provided by neuroimaging are relatively crude and non-specific and, thus far, have no t been related to specific underlying cellular mechanisms. The current proposal has two main aims: First, to investigate the functional and clinical significance, timecourse, and age-dependence of experience-dependent white matter and grey matter change. Second, to carry out parallel neuroimaging and histological studies in rodents in order to determine mechanisms underlying change detected on imaging. The results of the animal studies will be relevant not only to those with an interest in plas ticity but also to the wider imaging community, as they will shed light on the anatomical basis of structural imaging measures.

Amount: £187,532
Funder: The Wellcome Trust
Recipient: University of Oxford

Robust workflow for sub-volume averaging of tomographic data. 03 Feb 2014

Viruses and their interactions with host cells provide attractive model systems for studying macromolecular interactions. The structural design of viruses provides a remarkable example of simplicity and functionality in biological systems. Viral particles work as highly effective molecular devices in the transfer of the viral genome and accessory proteins from infected to non-infected cells. I intend to address dynamic interactions of viral and cellular protein complexes leading to membrane curv ature perturbations in their native environment using cryo electron tomography and complementary approaches. We will concentrate on three major systems - (i) Viral and eukaryotic fusion proteins, (ii) cell-cell-transmission of retroviruses and (iii) cellular membrane coats - and study for each of them a particular aspect of membrane curvature modulation at various levels of detail and complexity. We will take advantage of the properties and specificities of the individual systems to understand t he underlying mechanistic properties of membrane remodelling. Furthermore, computational and imaging tools will be developed for the efficient analysis of the structural interactions of the macromolecules. The combination of systems and approaches ultimately aims to integrate high resolution structural information with live cell imaging to achieve a spatio-temporal description of complex biological processes thereby revealing native structure-function relationships.

Amount: £113,032
Funder: The Wellcome Trust
Recipient: University of Oxford

Hospital Alerting via Electronic Noticeboard (HAVEN) 24 Apr 2014

Hospitalised patients may suffer deterioration in their medical condition, or develop a complication of their illness such as a chest infection or life-threatening blood clot. Hospital staff monitor patients for these problems using “vital signs” such as temperature and blood pressure. However, in spite of advances in the way the vital signs are recorded and assessed, in the UK each year 40,000 inpatients deteriorate sufficiently to require admission to an intensive care unit, 10,000 of which subsequently die.Modern hospitals now collect much information electronically, including patient descriptors (for example age and previous admissions), laboratory results, and vital signs. When clinicians assess patients they mentally weigh up each of these pieces of information to gauge how ill the patient is at the time, and their likely future course. Clinicians and clinical managers can only do this one patient at a time.A research group at the University of Oxford headed by Dr Peter Watkinson plans to produce a hospital-wide IT system that makes this risk assessment in all hospital patients continuously. The score will be made available via a display specifically designed to allow expert clinicians to identify and rank at-risk patients quickly and initiate treatment. The aim is to deliver a validated prototype system ready for commercialisation in partnership with industry.

Amount: £656,612
Funder: The Wellcome Trust
Recipient: University of Oxford

Sacred water. 22 Jan 2014

'Sacred Water' explores people's relationship with water usage from ancient fountains around the Kathmandu Valley and risks of enteric disease. Through art and media we strive to build understanding between communities and medicalworkers. The project will be based on research on endemic urban typhoid transmission at the Oxford University Clinical Research Unit Nepal, Patan Hospital, Kathmandu. In collaboration with the Community Medical Assistants (CMAs) from OUCRU-NP, Lena and local artists from the Bikalpa Art Centre, will create a short film on usage and maintenance of the ancient fountains and develop an art workshop for local residence to express their relationship with water and water shortages. Building on the established relationship between CMAs and local patients, we plan to visit and film people in their homes and capture their activities surrounding the water spouts. With artists from the Bikalpa Art Centre, we will develop an art workshop for people to express their relationship withwater, water shortage and health concerns. By weaving together visual elements drawn from scientific research and those from people's imaginations we hope to gain some understanding of the discrepancies between science and real life practice. This in turn would provide continuing dialogue between the researchers and local people, and contribute to on-going efforts to improve sanitary conditions. The interactions and dialogues, the film and the art workshops will all contribute to build trust and understanding between the local communities,researchers and artists. This in turn will inform research agendas, future health interventions and build community empowerment.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £1,999,888
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £1,687,339
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 Cluster for the Development of Dynamic 3D Nanoscopy 05 Jul 2016

Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.

Amount: £729,183
Funder: The Wellcome Trust
Recipient: University of Oxford

Ebola Data Sharing Platform 30 Sep 2016

The purpose of the Platform is to assemble and harmonise all available clinical, laboratory and epidemiological data on Ebola virus disease in order to inform evidence based policy and practice; ultimately improving patient outcomes, reducing the impact of future outbreaks and saving lives. The impact of the Platform will extend beyond Ebola as a new model of governance for data sharing in tropical and emerging infectious diseases. The development and sustenance of this unique tri-partite collaboration partnership will open novel opportunities to implement research in emerging and re-emerging infections.

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Oxford

An Analysis Of The Animal/Human Interface With A Focus On Low And Middle Income Countries 30 Sep 2016

Fleming Fund: supporting surveillance capacity for antimicrobial resistance The animal/human interface with a focus on low and middle-income counties Stephen Baker – Oxford University Clinical Research Unit, Viet Nam Our core research themes aim to make defining contributions to the understanding of infectious diseases transmission and susceptibility; to develop new tools to prevent, control and treat antimicrobial resistant (AMR) organisms; improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and 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 deliver world-class research across these themes.

Amount: £21,091
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural analysis of unconventional kinetochore proteins in Trypanosoma brucei 08 Jun 2016

Faithful chromosome segregation is essential for the proliferation of all organisms. Although studies in popular model eukaryotes have found that macromolecular kinetochore complexes assemble onto centromeric DNA to facilitate segregation, it is not known whether this mechanism applies to all eukaryotes. To uncover fundamental principles of eukaryotic segregation machinery, I am studying kinetochore functions in Trypanosoma brucei, an evolutionary distant eukaryotic parasite. No kinetochore prot eins has been identified and thus how trypanosomes segregate their chromosomes remains a black box. In my pilot study, I carried out a localization-based screening and proteomics and identified 12 kinetochore proteins. In this proposal, I aim to identify the complete kinetochore proteomes in T. brucei. Identified kinetochore proteins will be characterized using various techniques both in vivo and in vitro to reveal the molecular mechanism of chromosome segregation in trypanosomes. By revealing w hich features are fundamental and which are species-specific, I aim to understand the design principles of kinetochores that facilitate chromosome segregation with exquisite accuracy. Understanding the mechanism of chromosome segregation in trypanosomes is also medically important to develop better treatment for these diseases.

Amount: £178,556
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Strategic Support Fund 07 Sep 2016

Not available

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

The NPC lysosomal pathway as a novel hub in host: pathogen interactions 05 Jul 2016

We have made the novel and unexpected discovery that the lysosomal pathway deficient in a rare genetic lysosomal storage disease (Niemann-Pick type C (NPC)) is a hub targeted by multiple human pathogens, including Mycobaterium tuberculosis and Ebola. Our aims are therefore to: 1) understand the molecular mechanisms by which pathogenic microbes manipulate NPC1 function, 2) determine the breadth of human pathogens that have evolved strategies to target this protein to promote their survival, 3) interrogate NPC1 and acidic store Ca2+ involvement in Ebola infection and further the identification of anti-viral molecules and 4) define the roles that lysosomal Ca2+stores play in regulating inflammatory responses. We anticipate the insights gained from these studies will expedite development of new approaches to infectious and inflammatory disease treatment.

Amount: £1,681,554
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: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Coordination of chromosome unlinking and segregation 05 Apr 2016

The objective is to understand mechanistically how the bacterial chromosome is organized and processed throughout the cell cycle, by addressing the molecular mechanism by which the SMC complex, MukBEF, acts in chromosome organisation and segregation. This will also generally inform mechanisms of SMC action, a crucial process in normal and pathological chromosome management in all organisms. The proposed research will use state-of-the-art methods to minimise ensemble averaging. By using quantitative live-cell single-molecule imaging that allows visualization of the assembly and action of molecular machines, alongside methods that allow the rapid production and removal of specific proteins, and which interfere with normal protein interactions, it will enable mechanistic in vivo biochemistry that will be complemented by elegant genetics and in vitro biochemistry. We will progress our work showing that the interaction between MukBEF and, TopoIV, is essential for timely chromosome unlinking, and that MatP, which binds multiple sites within the replication termination region, regulates the spatial cellular distribution of MukBEF and TopoIV. Finally, we will characterize the mechanism by which localised MukBEF clusters act to position and segregate newly replicated oris, while leading to global chromosome organization, timely chromosome segregation and efficient repair.

Amount: £1,625,956
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £1,279,523
Funder: The Wellcome Trust
Recipient: University of Oxford