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Recipients:
University of Oxford

Results

Core award for the East African Major Overseas Programme - KES portion 30 Jun 2016

Our application provides the platform for a uniquely inter-disciplinary scientific programme linking biomedical, social and health systems research to deliver scientific insights of global importance to human health. We will work based from Kenya (Kilifi and Nairobi) and Eastern Uganda (Mbale). The Kilifi Programme will tighten its focus on our integrated platform (i.e. linked hospital/demographic/molecular surveillance) and legacy of continuous epidemiological data and stored samples over 25 years. Work in Mbale will consolidate a leading centre of clinical investigation in an area of hyper-endemic malaria transmission, and the Nairobi Programme will increase its independence with a focus on international disease mapping and health systems. Our major scientific themes include vaccines (including pre and post-licensing studies with exploratory immunology and epidemiological components), genomics and infectious disease transmission, clinical research (focusing on multi-centre clinical trials and the pathophysiology of critical illness with a developing programme on neonatal and maternal health), public health (with an emphasis on spatio-temporal analyses) and health systems research. The Programme is delivered by 29 PIs (i.e. scientists with independent funding). Training is central to our vision, and additional awards support 18 post-doctoral scientists and a projected 50 PhD students during the next 5 years.

Amount: £18,904,756
Funder: The Wellcome Trust
Recipient: University of Oxford

An Analysis Of Networks And Education Resources Supporting Drug Resistant Infection Surveillance In Low And Middle Income Countries 30 Sep 2016

Proposal for an analysis of networks and education resources supporting drug resistant infection surveillance in low and middle income countries Applicant: Elizabeth Ashley MRCP (UK), FRCPath, PhD Organisation name: University of Oxford P art 1: Networks Objective: Identifying networks dealing with surveillance, monitoring and analysis of resistance in low and middle income countries, including networks supporting quality assurance, which currently exist or have existed over the last fifteen years, suggest factors which are important to achieving impact, success and sustainability. Background There is no readily accessible, comprehensive source of reliable data on antimicrobial resistance (AMR). Networks concerned with surveillance, monitoring and analysis of AMR in low and middle income countries (LMICs) may be national, regional or global. A number of networks and initiatives concerned with AMR have been established over the years, the majority of which have not survived [1,2]. Networks may adopt different approaches to surveillance, varying in terms of geographical coverage, restriction to isolates from normally sterile sites e.g. blood cultures only, or with a focus on single versus multiple pathogens. The choice of approach might reflect the public health priority of tackling a particular disease in an area, surveillance for epidemics, vaccine development by the pharmaceutical industry or a research agenda.

Amount: £21,374
Funder: The Wellcome Trust
Recipient: University of Oxford

Prime-Target Vaccination in Malaria 08 Apr 2016

1. Can a more protective liver-stage vaccine against P. falciparum malaria be identified by assessing antigens using transgenic parasite technology combined with sequencing of parasite peptides eluted from MHC molecules? 2. Can this liver-stage vaccine be improved by combining it with an new virus-like particle-based anti-sporozoite vaccine? 3. How can these pre-erythrocytic components be efficiently integrated with anti-blood-stage and anti-sexual stage vaccine components to develop a hig hly effective multi-component malaria vaccine?

Amount: £201,600
Funder: The Wellcome Trust
Recipient: University of Oxford

In vivo investigation of the PARP-1 regulator, HPF1/C4orf27 04 Aug 2016

Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the molecular players involved in these pathways and their mechanism s of regulation remain poorly understood. In recent years, blocking the PARP-regulated pathways using small-molecule inhibitors has become a promising strategy for treatment of cancer and acute cardiovascular conditions. For example, cell-permeable inhibitors targeting the PARP enzymes involved in DNA break repair demonstrated efficacy against certain types of cancer, such as hereditary breast or ovarian cancers. The intriguing alternative approaches to the chemical inhibition of PARPs include t argeting downstream protein effectors of PARP signalling and targeting PARG, the major enzyme that removes poly(ADP-ribosyl)ation. In the proposed studies, we will utilise a combination of biochemistry, cell biology and structural studies to improve our understanding of the function and regulation of PARG enzyme, and also to attempt developing the first specific cell-permeable human PARG inhibitors. Another goal of our studies is to screen for novel PARP-regulated DNA repair factors. Some of the identified proteins will be further characterised to elucidate their exact biochemical functions and regulation in DNA repair. Furthermore, we will explore the potential of these proteins to be exploited as targets for small molecule inhibitor design and cancer therapy.

Amount: £165,310
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

Becoming Good: Early Intervention and Moral Development in Child Psychiatry. 30 Sep 2016

This project investigates the emergence of the early intervention paradigm in developmental child psychiatry through a set of linked studies that reveal and critically examine the paradigm's discursive logics, its translational dimensions and its ethical implications. The project focuses on those dimensions of the early intervention paradigm that relate explicitly or implicitly to moral development in children, and which propose biological, social or biosocial interventions at the prodromal stag e. Key Goals: * To explicate the key arguments of the early intervention paradigm in developmental psychiatry, and to contextualise psychiatric knowledge production within a broader social field of early child care concerns * To investigate young people's perspectives in consideration of the harms and goods of early intervention into child moral development and moral conduct * To provide an original empirical investigation of an epigenetics-based early intervention programme for fami lies * To reflexively develop and deploy an empirical ethics approach to guide normative analysis of early intervention strategies into child moral development * To contribute methodological innovations in research methods with children * To provide opportunities for substantive, multi-disciplinary engagements among scholars at various career stages * To build capacity in empirical ethics and related bioethics areas * To support the inclusion of families and young people in debate s about the social and ethical impacts of early intervention into child moral development and moral conduct

Amount: £35,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining the role of hypoxia inducible factors in viral replication and pathogenesis 05 Apr 2016

Viruses are obligate parasites that have evolved to manipulate their host to their advantage. Hypoxia inducible factors (HIFs) are regulated by oxygen-dependent and independent stress signals and control genes involved in energy metabolism, inflammation and angiogenesis. HIF-signalling pathways are perturbed in many diseases including cancer and inflammatory conditions, however, their role in viral infection is poorly understood. My group’s recent discovery that HIF-1alpha regulates HBV and HCV infection highlights an unexpected role for these transcription factors in the replicative lifecycle of these liver-tropic DNA and RNA oncogenic viruses. We have shown that HBV and HCV activate HIF and associated-transcriptional activity, suggesting a role in viral-associated cancer. We will use state-of-art HBV and HCV replication model systems, inducible-HIF hepatocellular knock-out mice, HBV transgenic mice and samples from human HCC to dissect the role of HIFs in virus replication and pathogenesis. Of note, several other oncogenic viruses (EBV, KSHV, HPV) also stabilize HIF, highlighting a convergence of diverse viruses targeting this pathway. Since viruses replicate in tissues with variable oxygen tensions in vivo, understanding the role HIFs play in viral replication will inform the design of physiologically relevant systems to model virus-host interactions.

Amount: £1,507,759
Funder: The Wellcome Trust
Recipient: University of Oxford

A mechanistic understanding of the replication of Influenza Virus 05 Apr 2016

The proposed research aims to extend our basic structural understanding of the polymerase of Influenza virus (FluPol). FluPol has two functions: to replicate the viral RNA genome and to transcribe viral mRNA, which require different initiation and termination strategies and the control mechanisms involved remain poorly characterised at the molecular level. However, it is currently unknown how FluPol is activated, in order to initiate primer-dependent transcription or primer-independent replication. Recently we, and others, have solved the first high-resolution structures of FluPol, allowing me to address some of these fundamental questions. By integrating a complementary set of structural, biophysical, biochemical and cell biological approaches, my long-term vision is to obtain complete mechanistic models with atomic-level detail of FluPol at key stages in the viral cycle. Using a combination of x-ray crystallography and single particle cryo-EM we will image trapped states of FluPol, in complex with different RNAs and nucleotides. In addition we will image RNPs before and after replication and transcription, using EM single particle imaging and tomography, to solve the structure of symmetric portion of RNPs, allowing the modeling of viral RNA, and allow us to reconstruct the asymmetric FluPol in the context of the RNP.

Amount: £1,110,478
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

Structure-based Engineering of Next Generation Meganucleases for Genome Editing 01 Sep 2016

Nucleotide repeat disorders comprise some of the most devastating rare diseases in the world. Currently there are no approved treatments for many of these diseases while approved drugs are palliative in nature, outlining an unmet need. A potential therapeutic approach involves engineering naturally occurring homing endonucleases to accurately target a unique sequence containing the edge of the repeat region as well as the repeat itself. This project represents a partnership between Precision Biosciences and Wyatt Yue's laboratory at the Structural Genomics Consortium. The working hypothesis is that the DNA break within the direct repeat will be repaired by single strand annealing (SSA), where the repeat on one side of the break pairs with another copy of the repeat on the other side of the break, resulting in a net reduction in the number of repeats. The project aims to generate a nuclease to target the CTG repeat expansion in the DMPK gene which causes the trinucleotide repeat disorder myotonic dystrophy type 1 (DM1). The partnership will combine structural, biochemical and biophysical methods to characterize the binding of nucleases to the appropriate repeat DNA sequences, generating key information for the development of a therapeutic nuclease for DMl.

Amount: £100,782
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Neuroscience 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Immunology, Infection and Translational Medicine 30 Sep 2016

Oxford - Immunology, Infection and Translational Medicine

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Immunology, Infection and Translational Medicine 30 Sep 2016

Oxford - Immunology, Infection and Translational Medicine

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Genomic Medicine and Statistics 30 Sep 2016

Oxford - Genomic Medicine and Statistics

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Neuroscience 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Genomic Medicine and Statistics 30 Sep 2016

Oxford - Genomic Medicine and Statistics

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - OXION 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Genomic Medicine and Statistics 30 Sep 2016

Oxford - Genomic Medicine and Statistics

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Neuroscience 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford