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Award Year:
2017
Recipients:
University of Oxford

Results

Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017

Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.

Amount: £99,994
Funder: The Wellcome Trust
Recipient: University of Oxford

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Role of lipid-reactive T cells in skin homeostasis and disease 28 Nov 2017

Immunological mechanisms underlying the maintenance and function of human skin during homeostasis and inflammation remain poorly understood. The majority of our existing knowledge of human cutaneous T cell immunology is based on the study of peptide-specific T cell responses. However, recently it has become clear that T cell responses to lipid-based antigens make major contributions to normal physiology and inflammation in the skin. Specifically, the Major Histocompatibility Complex (MHC) class I-like molecule, CD1a, is highly expressed in human skin. Through collaborative studies, we have recently shown CD1a is able to present lipid antigens to skin T cells, contributing to the inflammatory skin response. The timing is therefore now ideal to address the underlying mechanisms in order to inform new approaches to treatment. In this multinational collaboration, with each principal investigator bringing complementary expertise, reagents and/or cohorts, we aim to investigate the role of lipids in human skin-based immunity. Our interdisciplinary approach will encompass lipidomics, chemistry, clinical dermatology, cellular immunology, and structural biology to identify and characterise the key parameters that define skin-based immunity to lipids. Such information will directly inform disease mechanisms and translational studies aimed at treating inflammatory skin diseases.

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

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £742,082
Funder: The Wellcome Trust
Recipient: University of Oxford

Forecasting dengue cases: Vietnam as a case study 19 Jun 2017

Vector-borne infectious diseases continue to be a burden to Vietnam’s economy and population health. Understanding the spatiotemporal patterns of the disease transmission is thus vital for planning resources and targeting control measures. In this work, we propose a large-scale study on how different factors interact and contribute to the dynamics of dengue in Vietnam. We will employ multiple modelling techniques to analyse the dynamics of the disease and how to best predict future cases. We hypothesise that urbanisation has played a significant role in deriving the distribution of the Aedes mosquito and on dengue transmission, and will therefore incorporate factors about urbanisation gained from satellite images into predictive models. These models will use three main methods: statistical, mechanistic and machine learning. The key goal is to predict the number of new dengue cases as far as possible, and we will work in collaboration with those who use the forecasts to assess the most useful timeframe and accuracy. A particular aim will be the prediction of upcoming hotspots of dengue transmission so that hospitals can plan their resources. We will work to present the results clearly so they can best be used to help to reduce dengue burden in Vietnam.

Amount: £82,952
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £2,228,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the mechanisms and elements responsible for nuclear compartmentalisation during gene regulation. 31 Jan 2017

The genome is organised into a highly ordered and complex structure. It is separated into distinct regulatory compartments which have a functional impact on transcriptional regulation. CTCF has been found to act as a boundary, with the ability to block enhancer-promoter interactions and insulate regulatory territories. The process that creates and regulates this genome organisation is not well understood, therefore, the main aim of the proposed research is to investigate the role of CTCF, enhancer and promoter elements in generating and defining regulatory domains. To achieve this, we will initially expand a series of models mutating the CTCF sites within the well characterised mouse alpha-globin locus, and explore genome-wide, polymorphic CTCF binding sites between inbred mice strains. The effects on local chromatin and transcription will be assessed using a combination of standard genomic assays used within the Hughes group, and the chromosome conformation capture technique NG Capture-C developed by them. To complement this, we will use genetic engineering to find the minimal requirements for compartment formation using the well-characterised functional elements from the mouse alpha-globin locus out of their native chromosomal context, to define the basic rules underlying their formation.

Amount: £35,176
Funder: The Wellcome Trust
Recipient: University of Oxford

Delineating meiotic gene expression of male mice 31 Jan 2017

The mechanisms of meiosis have important consequences for the evolution, fertility, and speciation of sexually reproducing organisms. However, the full gene expression programme of meiosis is not currently known, partly due to heterogeneity of the cell population which is averaged by bulk tissue RNA sequencing or micro-array analysis. It has recently become possible to transcriptionally profile thousands of single cells using RNA sequencing, raising the possibility of identifying the gene expression profile associated with different stages of meiosis and hence delineating the full gene expression programme. The identification of genes expressed in meiosis and its sub-stages may aid in the discovery and understanding of meiotic mechanisms. I will use pseudotime ordering and latent factor analysis type methods to analyse this data and comprehensively define the transcriptional profile of male meiosis.

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

Statistical models of gene-environment interactions 31 Jan 2017

This PhD focuses on developing statistical methods to discover gene – environment (G-E) interactions. To date there has been some interest in testing for G-E interactions in animal models, but limited success in uncovering examples of G-E interactions in humans. This is in part due to the problem of exposure assessment, or rather, because representative data on the environment of a number of individuals over a lifetime has been hard to acquire. However the data recently made available by the UK BioBank, on over 500000 individuals and a wide array of environmental covariates, may now make it possible to detect these interactions. We aim to use a Bayesian methodology to first test a number of known models, such as a random effects model, against the dataset. We will then attempt to use a Gaussian Process Regression model to identify covariates involved in G-E interactions. This approach is advantageous as GPR is non-parametric, thus avoiding the curse of dimensionality, and places no assumptions on the order of interactions. However as this method currently scales in a cubic manner following the number of samples, significant computational challenges remain.

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

Understanding the cellular and molecular basis of epithelial migration using the Angiomotin mutant 31 Jan 2017

Epithelial morphogenesis is a complex process involving tissue-level integrity and dynamically coordinated morphogenetic change. The visceral endoderm (VE) in the mouse embryo is one such tissue that undergoes morphogenesis required for embryonic development. In angiomotin (amot) mutants, there is a characteristic abnormal furrowing in the anterior VE accompanied by aberrant apical build up of actin. This leads to reduced displacement of anterior VE cells and embryonic lethality. We do not understand the cellular and molecular basis for abnormal cell migration in this mutant, nor what proteins AMOT interacts with in this context. To address these questions, I will initially make detailed quantitative observations of cell behaviour by analysing light sheet and confocal microscopy data, using automated cell segmentation and tracking approaches I am developing. I will explore actin dynamics using FRAP and laser ablation on mutant and wild-type embryos. To understand the molecular pathway through which AMOT regulates epithelial cell behaviour, I will use a phosphoproteomic approach to identify interacting proteins using wild-type and amot mutant ES cell-derived embryoid bodies. Select interacting proteins will be tested for their role using small molecule inhibitors where available, or CRISPR mediated mutagenesis in ES cells and mice.

Amount: £31,026
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating a role for Z-nucleic acid binding in virus-host interactions 31 Jan 2017

Z-DNA is an alternative conformation of the DNA double helix. The existence of proteins containing Z-DNA binding domains (ZBDs) suggests that nucleic acids in this conformation have important but so far uncharacterised biological functions. One such protein is the innate immune protein Z-DNA binding protein-1 (ZBP1/DAI/DLM1). We have evidence that ZBP1 mediates virus-induced necroptosis in a manner dependent on its ZBD. This function of ZBP1 is sensitive to RNase but not DNase treatment, suggesting that the trigger is Z-RNA. We therefore hypothesise that Z-RNA may represent a novel pathogen-associated molecular pattern sensed by ZBP1. The aim of my PhD will be to further characterise this role of ZBP1 and to investigate the source and nature of the Z-RNA being sensed. In particular, we will ask if this Z-RNA is of viral and/or cellular origin, and whether specific sequence motifs are recognised by ZBP1. Another question pertains to the relevance of ZBP1 in diverse human virus infections. In parallel to these in vitro studies, we are developing a knock-in mouse in which the ZBD of ZBP1 is mutated. I predict that these animals will be less able to control viral infection due to a failure of ZBP1-mediated virus-induced necroptosis.

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

Enhancing the WT MOP Vietnam's Engagement Programme 30 Aug 2017

In 2015 the WT Major Overseas Programme Vietnam was awarded a renewal of its Core funding. The MOP has a history of successful public engagement, funded through International Engagement awards and from industry sponsorship. However, with the introduction of the Provisions for Public Engagement funding scheme, we applied for funding for engagement at an institutional level, enabling us to create a 5-year strategic plan for developing engagement capacity within the MOP and in the region. Now, 20 months into the award, we reflect on activities to date, and plan strategically for the second part of the programme. The 5-year public engagement programme includes a schools engagement programme (SEP) and a capacity building programme (CBP), both of which have proved to be very successful and highly valued by our local government and school partners. The third focus has been to develop researcher capacity for engagement – through small grants and offering training and mentoring. We have had a good uptake of these ‘seed awards’ from MOP researchers and increasing interest in engagement from researchers at local institutes in Vietnam. Schools Engagement: The SEP has been very successful (http://www.mediafire.com/file/td3kaomtu9t7ia7/Application.7z), in particular: afterschool science clubs; weekly science articles in a children’s magazine; science theatre; and lab visits enabling young people to interact with scientists. The SEP has also included ‘I’m a scientist, Get me out of here’ - a competition linking children and scientists, run with Gallomanor UK (https://imascientist.org.uk) (https://www.youtube.com/watch?v=n--SJOtFm1w). Capacity building: The CBP was developed in recognition that much of the ‘front-line’ contact with patients and communities enrolled in clinical trials or cohort studies is from hospital or government study staff. In response we have started a CBP to train and support hospital health care workers (HCMC), community-based data collectors (Nepal) and local vets (in provinces where we conduct research on zoonosis). As the funding for the IAS project and other awards come to an end, we need additional funding to support the current PE team. This application is for additional staff salary costs and to run PE workshops to develop engagement capacity across the region.

Amount: £343,289
Funder: The Wellcome Trust
Recipient: University of Oxford

DNA origami: how do you fold a genome? 30 Apr 2017

Recent advances in DNA sequencing technology mean that it is now possible to identify genetic variants in patients with specific diseases which either cause or alter their risk of developing that disorder. However, linking these variants to the genes they regulate and the symptoms of the condition itself is time-consuming and challenging. The overarching aim of this project is to develop high-throughout methods to systematically investigate the impact of genetic variants associated with specific diseases on cell function and human health. This will be achieved via collaboration between several groups within the University of Oxford and multidisciplinary external groups, each bringing their own specific field of expertise relevant to the overall aims of the project. Over the past three years, we have developed and refined high-throughput techniques to link genetic variants to the genes they control, and analyse how and why these variants impact the activity of their target gene. Now that we have established these methodologies and associated computational analysis pipelines, we will apply these techniques to variants associated with various conditions during the next two years of the award. In the first instance, these will be disorders associated with red blood cells, multiple sclerosis, and type 2 diabetes. The final stage of the project is to optimize recently developed genome editing techniques to correct any variants that are found to have a functional impact on the condition in question. This will serve two purposes; first it will prove that the variants influence gene regulation and second it will provide the first steps to establishing proof-of principle for gene editing as a potential therapeutic opportunity. Of particular importance to the interpretation of this work will be ongoing basic research in modeling and visualization of how gene activity is regulated in the 3D space of the nucleus, which will aid our understanding of how these specific variants affect the activity of distant genes. Using state of the art methods to visualize and interact with the DNA molecule in three dimensions represents a unique opportunity to intuitively explain these complex but universally important concepts to the public.

Amount: £35,850
Funder: The Wellcome Trust
Recipient: University of Oxford

The Ethics of Genome Editing in Livestock 17 Jul 2017

Genome editing in livestock (GEL) could potentially be used to mitigate urgent global problems of infectious disease, antimicrobial resistance, global warming, and animal suffering while also increasing agricultural productivity. Despite its imminence and potentially transformative potential, there has been minimal ethical debate about GEL. This project will provide the first in-depth philosophical analysis of GEL, focussing on four questions on which such research is most urgently needed: (1) How far do ethical concerns raised in relation to conventional genetic engineering using previous techniques carry over to GEL? (2) Are the arguments in favour of GEL best understood in terms of cost-benefit analysis, an obligation to 'arm ourselves for the future' or an obligation to correct past complicity in unethical agricultural practices? (3) How should duties to animals be understood in the context of GEL, and what is the relative importance of welfare, respect, and avoidance of commodification? (4) Would application of GEL to improve human and animal welfare entail complicity in maintaining unethical agricultural practices and if so, how could this complicity be reduced or offset? I will then investigate how my findings bear on how GEL should be regulated, and on related areas of public policy.

Amount: £227,968
Funder: The Wellcome Trust
Recipient: University of Oxford

Healing Heathen Lands: Protestant Missions and Public Health in British India, 1855-1956 17 Jul 2017

This project will explore the role of Protestant missions in the making of British Indian public health by tracing the interactions between evangelical, colonial and vernacular sources. It will argue that Protestant missionaries in South Asia did not merely play a complementary role to imperial biomedicine. It will examine the ways in which missions contributed towards shaping colonial health policies as well as knowledge of colonial disease and treatment. The project would also explore the extent to which Indians and their knowledge was involved in medical missions. This work will add on to histories of imperial medicine, international health, global history, colonial Christianity and postcolonial studies. The key goal of the project is to produce a monograph explaining the distinctiveness and significance of Protestant missionary medicine in South Asia. The project will be contributing to the emerging literature on British voluntary religious organisations in the making of imperial public health. It will also contribute to the broader literature on the relationship of modern science and medicine with Christianity.

Amount: £174,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Control of T cell responses by accessory receptors revealed by phenotypic models 11 Jul 2017

T cells orchestrate immune responses crucial for the elimination of infections and cancers. They do this by initiating a diverse set of effector responses when their T cell surface receptors (TCRs) recognise these threats. It is now appreciated that a large number of other, "accessory", receptors shape these responses. Indeed, the remarkable clinical success of checkpoint inhibitors and chimeric antigen receptors is based on perturbing accessory receptor signalling. Despite extensive research into the underlying biochemistry, we have yet to formulate canonical models of signalling that can predict how accessory receptors shape T cell responses. Here, we propose to use a mathematical method known as adaptive inference to identify signalling models directly from T cell response data, without prior biochemical assumptions. The method produces what we term phenotypic models because it coarse-grains over molecular information. These models provide effective pathway architectures showing how accessory receptors integrate (or not) with TCR signalling to shape response phenotypes. This will move the field beyond the current stimulatory/inhibitory binary paradigm of accessory receptors. The work offers a different way to study receptor regulated signalling pathways and the predictive power of the phenotypic model will be exploited for T cell-based therapies.

Amount: £1,783,754
Funder: The Wellcome Trust
Recipient: University of Oxford

Vacation Scholarships 2017 - University of Oxford 16 Jun 2017

Vacation Scholarships 2017-University of Oxford

Amount: £15,500
Funder: The Wellcome Trust
Recipient: University of Oxford

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

A realist review of community engagement with health research 07 Dec 2017

The project will conduct a comprehensive review of community engagement using a realist review approach appropriate for tackling the conceptual complexity and practical diversity of the field. A review team with worldleading expertise in the theory and practice of CE will be supported by an advisory panel of internationally renowned realist review scholars. The review will begin with engagement with malaria research as a ‘pathfinder’ topic – and draw on a network of content experts, implementers and funders to input into and validate the review, ensuring its findings are widely disseminated and embedded in international CE work. Wellcome, BMFG and leading global health funders and implementation partners will benefit from a consolidated evidence base to underpin development of CE strategies in global health research and interventions. Outputs will include articles in peer reviewed open-access journals, an accessible evidence base on MESH/HELP, including context-relevant guidance for developing and evaluating CE strategies, and a critical mass of academics, practitioners, implementers and funders with a mutual interest in strengthening the theory and practice of engagement. In this way the review will spearhead the beginnings of a ‘science’ of community engagement and outline a clear value proposition for CE in global health research (14).

Amount: £260,250
Funder: The Wellcome Trust
Recipient: University of Oxford

Reducing risk of recurrent stroke and cognitive decline after TIA and stroke through characterisation and treatment of novel physiological markers 25 May 2017

Despite optimal medical management, there is significant post-stroke residual risk of recurrent cardiovascular events and cognitive decline. This fellowship aims to reduce this risk through characterisation and modification of novel physiological factors, including BP variability and cerebrovascular pulsatility, whose relative prognostic significance is currently unclear but which represent potential therapeutic targets to further reduce cardiovascular risk. I will develop and lead the Cardiovascular Laboratory in the new Centre for Prevention of Stroke and Dementia, measuring BP variability, arterial stiffness, autonomic, cerebrovascular and endothelial function and chronic cerebrovascular injury on MRI to: l. Detemine these physiological indices' relative prognostic significance for cerebrovascular events and vascular-type cognitive decline in 1000 Oxford Vascular Study patients, creating the largest fully-phenotyped cohort after TIA and stroke with clinical, cognitive and physiological follow-up; 2. Test potential treatments in exploratory randomised trials, including antihypertensives (amlodipine/losartan/atenolol) and vasodilators (sildenafil/hydralazine); 3. Assess drug tolerability and novel intermediate endpoints for future potential phase 3 trials ; 4. Develop the skills and facilities to manage large, physiologically-guided clinical trials, testing novel interventions to treat well characterised physiological effects; leading to phase 3 trials assessing effects of novel treatments on cardiovascular risk and chronic cerebrovascular injury in stage 2 of the fellowship.

Amount: £745,578
Funder: The Wellcome Trust
Recipient: University of Oxford