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Recipients:
University of Oxford

Results

How do CHRND mutations disrupt AChR cluster formation? 27 Apr 2017

The project aims to utilise mutations identified in congenital myasthenic syndromes to study the interactions of the muscle acetylcholine receptor (AChR) and its anchoring protein, Rapsyn.Widely quoted publications suggest that Rapsyn interacts with the M3-M4 intracellular loop of the AChR alpha, beta and epsilon subunits, however we have identified several kinships in which mutations in the M3-M4 intracellular loop of the AChR delta subunit underlie a phenotype that mimics myasthenic syndromes caused by mutations in RAPSN. The project will use in vitro mutagenesis and cell culture experiments to investigate how mutations in CHRND impair agrin induced-AChR clustering in C2C12 myotubes. Variants identified in CMS patients, ie. p.(Glu381Lys) or p.(Arg376His) will be incorporated into expression constructs and transfected in chrnd-/- C2C12 cell that have been created using CRIPR/Cas9 techniques. Similar experiments will be performed following in vitro mutatagenesis that is designed to disrupt potential PKA, PKC and tyrosine kinase phosphorylation sites within the M3-M4 intracellular loop of the delta subunit. The effects of the mutations on agrin-induced AChR cluster formation will be assessed by using fluorecent-labelled alpha bungarotoxin and microscopy. This short project will provide novel data on how mutations within the AChR itself can impair the cluster formation.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishing a feeder EM facility for South Parks Road Oxford 05 Apr 2016

In the last two years a convergence of a new generation of cryo-electron microscopes, with the first generation of direct electron detectors, and new algorithms for image analysis have enabled the routine determination of the structure of macromolecular complexes by EM. It is now possible to look directly at molecules as small as 150-200 kDa with an electron microscope and determine their atomic resolution structure; even more revolutionary, tomographic methods allow direct imaging of the internal machinery of cells at the level of single molecules. These advances are bridging the resolution gap between light microscopy and molecular structures. The goal of this proposal is to make our own research part of this revolution. We request funds to purchase two cryo-EM that will allow the collaborative group immediately to accelerate their own research and to nucleate an advanced cryo-EM facility in the South Parks Road science campus of Oxford University. This facility is also part of an Oxford-wide strategic plan, further integrating structural biology, and ensuring that the co-PIs, and others, can effectively generate the preliminary data needed to justify access to the Titan KRIOS microscopes that are now installed at Harwell as a national facility.

Amount: £2,146,619
Funder: The Wellcome Trust
Recipient: University of Oxford

Burden of Zika virus in different South East Asian populations with febrile illness. 30 Sep 2016

Our planned studies will identify if ZIKV is a current and neglected problem in three SE Asian populations located in Thailand, Vietnam and on the Thailand Myanmar border. Although ZIKV is reported to be endemic in Asia its prevalence and true significance in South East Asia is not well characterised. Transmission of ZIKV Myanmar has not yet been reported, there have only been two confirmed cases recently reported in Vietnam and there are only seven published confirmed cases of ZIKV infections in Thai residents (these were reported by the Thai Ministry of Public Health in 2015). There are several cases of confirmed ZIKV infections from travellers returning from Thailand, indicating that ZIKV is an under and/or misdiagnosed infection in this country. Further work is therefore urgently required. This is important not only for local public health planning, but also from a global health perspective as travellers to and from these regions may be at risk of infection with associated complications and/or pose a transmission risk to naïve populations.

Amount: £10,000
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

(Pilot) Parenteral interventions to support families of children with neurodisability in low resource settings 16 Nov 2015

I plan to conduct cross sectional surveys in five demographic surveillance sites across sub-Saharan Africa, to identify cases of active convulsive epilepsy (ACE). This cohort will be used to determine the prevalence of ACE and the extent of the number of people not receiving treatment (treatmetn gap) in these sites, identify the causes (particularly parasitic diseases that could be prevented) and establish cohorts of people with epilepsy, from which the magnitude and causes of excess mortality a ssociated with epilepsy can be determined. In addition, a community based intervention will be tested through a randomised cluster trial in one of the sites, to reduce the treatment gap and improve the quality of life of people with epilepsy in this area.

Amount: £28,916
Funder: The Wellcome Trust
Recipient: University of Oxford

Identification of T-cell epitopes for vaccine targets against melioidosis in North East Thailand. 30 Sep 2016

A greater understanding of immunity to infectious diseases is desirable to improve treatments and vaccine design, especially for intra-cellular organisms which are harder to prevent and cure. One such organism is Burkholderia pseudomallei, a Gram negative bacterium which causes melioidosis in humans which carries a high mortality. The goal of this study is to demonstrate the CD8 response in patients acutely unwell with melioidosis and define key epitopes for vaccine design. 280 patients with ac ute melioidosis in North East Thailand will be studied, both with and without diabetes mellitus. Peripheral blood mononuclear cells will be isolated locally and used to evaluate T-cell responses by ex vivo IFN-gamma ELISPOT and flow cytometry to a panel of candidate proteins and peptides from B.pseudomallei. Cells from people with diabetes in the region and from unexposed healthy control subjects will be used as controls. Information from HLA typing and from the current consortium at the Immune Epitope Database will be used to identify candidate proteins and peptides, and responses to 9-mer peptides will be studied. Other studies of neutrophil function and acute phase response will be studied in parallel to produce a unified dataset covering several aspects of innate and adaptive immune responses.

Amount: £241,835
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

Open access block grant award 30 Sep 2016

Not available

Amount: £85,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The Place of Meat and Dairy in Global Healthy and Sustainable Diets 24 Mar 2016

The transition to diets rich in meat and dairy is occurring at different rates throughout the world. It is a key driver of the increase in mortality and morbidity associated with diet-related disease and also of the increasing impact of food production on the natural environment. It also has huge cultural and economic significance. It is commonplace today to call for "food system thinking" when considering how diets might be changed to improve heath and sustainability outcomes, but much more rare for this to be put into practice. We shall build an interdisciplinary food system team to show what changes in meat and dairy consumption will provide the greatest health and environment benefits and develop interventions to help bring them about. Our programme will develop innovative global health models, based on novel epidemiological data, to radically improve policy development and provide multiple food system and environmental outputs. In both a developed and developing country setting we shall propose and test novel interventions for healthy and sustainable diets, understanding their interconnectedness and the social and political contexts underlying successful implementation. We shall provide an independent source of evidence to inform debates on meat and dairy.

Amount: £25,200
Funder: The Wellcome Trust
Recipient: University of Oxford

Development of a Generalized Modules for Membrane Antigens vaccine against gonococcus 13 Jan 2016

There are 106 million cases of gonorrhoea each year that disproportionately affect women and new-born children, particularly in low-income countries. With increasing levels of anti-microbial resistance, there are growing concerns about untreatable gonorrhoea. There is a clear need for a vaccine against gonorrhoea, but none is available. Cal’s solution is to develop a Generalized Modules for Membrane Antigens (GMMA) vaccine candidate for gonorrhoea. It will exploit the ability of Gram-negative bacteria to shed outer membrane blebs displaying antigens including lipo-oligosaccharide and multiple membrane proteins which are targets of functional/bactericidal immune responses. GMMA are easy to manufacture and highly affordable. They are more immunogenic than equivalent subunit vaccines, having an adjuvant effect through delivery of signals to the innate immune system. The key goal of the project is to establish preclinical proof-of-concept for suitability of the GMMA approach for vaccine against gonorrhoea. The future potential healthcare benefits are a major global reduction in gonorrhoea, and improvement of reproductive and maternal/new-born health.

Amount: £167,275
Funder: The Wellcome Trust
Recipient: University of Oxford

University of Oxford - Chromosome and Developmental Biology 30 Sep 2016

University of Oxford - Chromosome and Developmental Biology

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 - 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 - OXION 30 Sep 2016

Not available

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

Characterization of SAMHD1’s evolutionarily conserved function(s) 30 Sep 2016

SAMHD1 is a protein that was identified as a human immunodeficiency virus type 1 (HIV-1) restriction factor. It prevents HIV-1 replication by degrading the intracellular pool of dNTPs by virtue of its deoxynucleoside triphosphohydrolase activity. SAMHD1 mutations were shown to cause Aicardi Goutières syndrome (AGS), a rare auto-inflammatory disease, and were found in chronic lymphocytic leukaemia (CLL). The protein is highly conserved, suggesting that it has evolutionarily ancestral functions in addition to HIV-1 restriction. The aim of my DPhil project is to identify these functions. Most recent publications and preliminary data from the host lab and collaborators suggest different possible functions for SAMHD1, including (i) restriction of DNA virus infection; (ii) control of endogenous retroelements; (iii) DNA replication and repair; and/or (iv) cellular nucleotide metabolism. I will test these hypotheses both in vitro and in vivo, using a wide range of techniques. This work may lead to a better understanding of SAMHD1’s functions and may provide new insights for the therapy of diseases such as AGS and CLL where SAMHD1 is mutated.

Amount: £27,523
Funder: The Wellcome Trust
Recipient: University of Oxford

Using next generation chromatin conformation capture approaches to study the dynamics and 30 Sep 2016

Gene expression is controlled by complex networks of regulatory elements in the genome, involving promoters, enhancers, silencers and insulator elements. Chromatin conformation capture methods can be used to analyse these cis-acting networks by measuring the physical interactions between the regulatory elements involved. Recently, a high-throughput approach, Capture-C, has been developed, that can be used to analyse such networks for hundreds of loci in the genome, at high resolution, in a single experiment. This project aims to use novel variants of Next Generation Capture-C to study (1) the dynamics of regulatory networks in different stages of haematopoiesis and (2) the three-dimensional structure of the genome.

Amount: £20,830
Funder: The Wellcome Trust
Recipient: University of Oxford

Subcortical-cortical integration 30 Sep 2016

"The aim is to undertake a multimodal approach to investigate subcortical-cortical integration in human and animal models at both functional and anatomical levels. By adopting a multi-technique methodology, this approach will allow me to study how subcortical (with a focus on the amygdala) and cortical (predominantly the prefrontal cortex) regions of the brain have evolved, how they are connected and interact. This knowledge is necessary to unravel the mechanisms underpinning cognition and sociality, as well as to explain how evolutionary pressure shaped the human brain. To address how limbic and cortical regions interact I propose to investigate both the anatomical and functional connectivity of subcortical-cortical circuits in humans and animals using MRI and to study alteration in neural activity resulting from focal lesions in the animal brain. Further insight into the mechanisms influencing subcortical-cortical interactions will be obtained by analysing socialdependent changes consequent to careful experimental manipulations of social dominance. The results of the proposed PhD plan will be relevant to both cognitive and comparative neuroscience. By directly manipulating cognition and behaviour, the results have the potential for being translated into an understanding of clinically relevant post-lesion brain plasticity and of psychiatric disorders."

Amount: £144,155
Funder: The Wellcome Trust
Recipient: University of Oxford