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Recipients:
University of Oxford

Results

Chloroquine/Hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis study (COPCOV) 30 Sep 2020

There is no proven treatment, chemoprophylaxis or vaccine for COVID-19. This is the most serious pandemic emergency for 100 years. Healthcare workers are being affected disproportionately in the continuing epidemic threatening an imminent breakdown of health services. Chloroquine and hydroxychloroquine are safe and well-tolerated medications which can be taken for years without adverse effects.Both have significant antiviral activity against SARS-CoV-2 and there is emerging evidence from China and Europe of efficacy in treatment. Unfortunately there is also premature recommendation from countries such as India which now recommends low dose hydroxychloroquine for prophylaxis in health care workers. We propose conducting a multi-centre, multi-country randomised, double blind, placebo controlled assessment of the prophylactic efficacy of chloroquine (Asia) or hydroxychloroquine (Europe) in preventing COVID-19 illness in at-risk healthcare workers and other frontline staff. At least 40,000 participants in Asia and Europe will be randomised 1:1 to receive chloroquine or hydroxychloroquine or a matched film coated placebo as daily prophylaxis for three months. The study’s objectives are the prevention of symptomatic coronavirus disease (COVID-19) and the attenuation of the clinical severity.

Amount: £6,920,135
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation of pre-existing immunity to coronaviruses; implications for immunopathology and pathophysiology of COVID-19 disease 30 Sep 2020

Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2 & MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2. Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses. Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to inform the immunopathology and pathophysiology of COVID-19.

Amount: £1,217,834
Funder: The Wellcome Trust
Recipient: University of Oxford

lvermectin Safety in Small Children 30 Sep 2020

lvermectin is a very safe and beneficial drug which is used for the treatment of more than a dozen different neglected tropical diseases (NTDs), many of which are associated with important public health problems. Current label indications for ivermectin prevent use in small children weighing less than 15kg, due to limited safety data in this group. Many of the NTD treatment options for small children rely on compounds that are less safe and/or efficacious compared to oral ivermectin. Our proposal will establish the safety and pharmacokinetics of escalating doses of ivermectin to treat scabies infected children weighing less than 15kg. The safety assessment will provide crucial evidence on the use of ivermectin for numerous diseases in children weighing less than 15kg. The information from measuring drug concentrations in the patients will inform the optimal dosing of this drug in small children. Assessment of the efficacy of ivermectin, compared to permethrin cream, for the treatment of scabies in small children can provide an important alternative treatment for this widespread disease.

Amount: £510,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms of spliceosome remodeling and splice site selection during the catalytic stage of mammalian pre-mRNA splicing 04 Mar 2020

The spliceosome produces mRNAs in two sequential transesterifications – branching and exon ligation. The post-branching C complex is remodeled by the ATPase Prp16 into the C* complex. Prp16 allows binding of the exon ligation factors Cactin and FAM32A, which stabilise docking of the 3’-splice site (3’SS) at the active site. While in yeast Prp18 is constitutively bound to C* spliceosomes, in humans Prp18 and other exon ligation factors of unknown function appear to engage the C* spliceosome in a transcript-specific manner. Here, I will reconstitute the C to C* transition in vitro in mammals and use biochemistry and cryo-electron microscopy to isolate and visualize novel intermediates and dissect the structural mechanisms by which Cactin, FAM32A, Prp18, and additional exon ligation factors cooperate to promote Prp16-mediated remodeling and to ensure correct 3’SS choice. In parallel, iCLIP studies will reveal where these exon ligation factors bind across all human pre-mRNAs and how RNA sequences around the splice sites determine the association of subsets of factors on specific pre-mRNAs. This work will elucidate how Prp16 drives remodeling of the human catalytic spliceosome and will investigate whether exon ligation factors regulate alternative splicing in a sequence-specific manner while proofreading 3'SS recognition during exon ligation.

Amount: £1,199,999
Funder: The Wellcome Trust
Recipient: University of Oxford

Politics, elections, and inclusive decision-making: Do political institutions affect health? 30 Sep 2020

Do political institutions influence the health of populations? Political institutions once seemed fixed and stable, but now appear to be flexible and open to change. This project seeks to uncover whether changing political institutions could affect health. Political institutions are the rules that govern who participates and how they participate in decision-making processes within societies; for example, they dictate who gets to vote and how votes are counted. Political institutions potentially affect health because they make governments more (less) responsive to what citizens want. However, this straightforward view of how political institutions affect health overlooks how democracies can privilege some voices over others (e.g., party donors may matter more than voters) and so universal suffrage may not necessarily deliver better health. This project will shed light on these questions through a series of empirical case studies. For example, I propose to examine whether political incorporation improves the health of formerly excluded groups, and whether their influence on policy decisions is weaker in majoritarian political systems than proportional representation systems because votes are counted differently. This project speaks to the sustainable development agenda by illuminating whether inclusive and representative decision-making institutions may accelerate progress toward ensuring healthy lives for all.

Amount: £201,914
Funder: The Wellcome Trust
Recipient: University of Oxford

Highly sensitive brain blood flow measurements using ultra-high field magnetic resonance imaging 04 Mar 2020

Blood flow is critical for maintaining the steady supply of oxygen and nutrients to the brain, and blood flow changes are present in a range of diseases including stroke and dementia. Conventional methods for in vivo blood flow mapping have limitations and often cannot be used for longitudinal monitoring or research. In this proposal I aim to develop highly sensitive imaging methods for measuring brain blood flow based on a non-invasive magnetic resonance imaging technique, arterial spin labelling, applied at ultra-high field. The main goals of this research are: To establish a robust platform for ultra-high field arterial spin labelling by developing novel approaches to overcome a range of technical challenges associated with this technique; To develop advanced imaging approaches which allow richer cerebrovascular information to be obtained, including high resolution angiography and vessel-selective imaging; To demonstrate the high sensitivity achievable with these novel methods by measuring changes in white matter perfusion in patients with vascular cognitive impairment, and probing the brain’s response to tonic pain at unprecedented spatial resolution. These new methods will be actively shared with local, national and international collaborators, enabling previously unfeasible clinical and basic science research studies to be performed.

Amount: £1,017,466
Funder: The Wellcome Trust
Recipient: University of Oxford

Analyses of paired host-virus genomic data to understand disease heterogeneity of chronic viral infections. 04 Mar 2020

Host and pathogen genetic variations are major causes of clinical outcomes of infectious diseases. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. However, there is strong theoretical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology. The major limiting factor to date has been the lack of cohorts with paired host-virus data. Recent technological developments and reductions in the cost of high-throughput viral sequencing from clinical samples have provided new opportunities to analyse host-virus genomic data generated from the same patients. In this project I propose to analyse paired host-virus genomic data from patient cohorts infected with HBV, HCV and HIV (clinically the most important chronic viruses worldwide) to answer the following questions: 1) What are the host genetic pressures driving virus evolution across different host populations and virus lineages? 2) What host and virus genetic interactions drive disease phenotypes? 3) What are the host genetic variants and pathways linked to disease phenotype across the three chronic viral infections of HBV, HCV and HIV?

Amount: £1,153,494
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the impact of ‘near-coding’ variation in human disease 04 Mar 2020

Rare diseases (prevalence 250 million people globally. Current approaches for identifying the genetic cause of a disease focus on regions of the genome that code directly for protein, finding a disease-causing variant in only ~50% of cases. My aim is to identify novel genetic variants outside of these protein-coding regions that lead to disease, and the mechanisms through which they do so. I will do this by applying computational and statistical methods to pioneering large-scale genomic datasets, totalling ~700,000 individuals. My approach will focus on ‘near-coding’ regions, defined as those directly adjacent to protein-coding sequence that have important functions regulating protein expression. I will use complementary approaches that (a) look for near-coding variants in rare disease patients without a causative coding variant and (b) assess the strength of negative selection acting on categories of near-coding variants to predict which are deleterious and cause disease. The findings from my work will be translated into clinical care to enable more patients to receive a valuable genetic diagnosis. In addition, increasing our understanding of the near-coding variant types that are deleterious will inform on genetic mechanisms underlying disease and suggest novel therapeutic strategies.

Amount: £828,055
Funder: The Wellcome Trust
Recipient: University of Oxford

Open Access Award 2019/20 30 Sep 2020

Not available

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

Open Access Award 2019/20 30 Sep 2020

Not available

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

Open Access (COAF) award 2019/20 30 Sep 2020

Not available

Amount: £1,157,238
Funder: The Wellcome Trust
Recipient: University of Oxford

Evaluating prevalence, incidence rates and mortality attributable to antibiotic-resistant bacterial infections and potential biases caused by underuse of blood culture in Wahidin Hospital, a tertiary-care hospital in South Sulawesi, Indonesia 19 Nov 2019

The burden of antibiotic-resistant bacterial infection (ARBI) in low and middle-income countries (LMICs) is largely unknown. Microbiology data is rarely analyzed and reported. Few publications available did not take account of bias caused by low number of blood culture utilization, categorize ARBI based on infection origin (community-onset or hospital-onset) and evaluate mortality attributable to ARBI. I propose to evaluate the situation of ARBI in a tertiary-care hospital in 2015-2018 in Sulawesi, Indonesia. I will analyze three routinely available data sets; including microbiology, hospital admission and antibiotic prescription data sets. I will use standard methods to estimate prevalence, incidence rates and mortality attributable to ARBI among bacteremia patients. I will categorize infection origin as recommended by WHO GLASS. I will evaluate and describe timing of blood culture collection and antibiotic prescription among patients who had parenteral antibiotic prescribed. I will evaluate whether reported parameters for ARBI were associated with timing of blood culture collection and antibiotic prescription. The results from this study will improve our standings on ARBI, diagnostic stewardship and antibiotic stewardship in Indonesia, and could be used to inform healthcare workers and policy makers in the country and other LMICs on resource allocation and intervention for actions against ARBI.

Amount: £120,000
Funder: The Wellcome Trust
Recipient: University of Oxford

An integrative, multiscale approach to understanding the molecular basis for receptor mediated trafficking within the early secretory pathway. 03 Dec 2019

The movement of proteins within eukaryotic cells is an essential process that maintains internal organelle integrity and underpins normal cell function. Despite the identification, several decades ago, of the receptors controlling protein trafficking, the molecular mechanisms of selective retention and export of ER and Golgi resident proteins still remain poorly understood. However, this recently changed when our study on the KDEL receptor revealed the structural basis by which a trafficking receptor can signal across a membrane to cytoplasmic coat protein complexes to initiate retrograde trafficking. We now aim to determine the mechanisms that underpin protein trafficking by other receptors within the early secretory pathway. We have developed an integrated approach involving cell biology and structure-based methods, including lipid-based crystallisation and single particle cryo-electron microscopy coupled with advanced protein engineering, super resolution light microscopy, and multiscale molecular dynamics analysis of trafficking complexes. Specifically, we will determine the mechanism for several cargo-receptor systems that control anterograde and retrograde protein sorting and address how sorting receptors recognise cargo proteins, and the mechanism(s) by which these receptors signal across membranes. Ultimately, we expect to understand the molecular basis for cellular trafficking, providing fundamental insights into crucial pathways involved in human protein folding diseases.

Amount: £3,027,479
Funder: The Wellcome Trust
Recipient: University of Oxford

Neural mechanisms underlying flexible behaviour 03 Dec 2019

I aim to understand how the brain represents the relationships between objects and events in the world, and how these representations can be generalised to allow flexible behaviour in new situations. By combining modelling with experiments in human and macaque, I will investigate these computations at both the cellular and systems level. We have developed models that abstract relational knowledge and predict detailed neuronal representations in rodent hippocampal-frontal circuitry. I will ask whether these building blocks can be extended to explain the sophisticated abstractions and inferences commonplace in primate behaviour. In primates, such abstractions compound hierarchically, and can be combined together, allowing deep inferences. To study these computations, I will develop novel tasks that are high-dimensional, yet amenable to mathematical description. I will use state-of-the-art techniques in humans, validated by high density cellular recordings in macaques, to study representations underlying abstraction, generalisation and inference in medial temporal and frontal cortices. In doing so, I will build new bridges between human and animal neuroscience, between biological and artificial intelligence, and new analytical and experimental tools for integrating across scales of neural activity. Developing such tools is important to bridge the precision of modern neuroscience to humans and thence clinical populations.

Amount: £2,844,723
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining Determinants of Intestinal Barrier Health and Disease 03 Dec 2019

IBD affects over 1.5 million and 2 million people in North America and Europe respectively. A significant proportion fail to respond to current treatments. In IBD genetic, environmental and intestinal barrier defects combine to precipitate dysregulated immune responses in the mucosa that manifest in disease. Recently we have utilized single cell technologies to chart the behaviour of diverse cell types making up the mucosal barrier in health and early diagnosis IBD. This has demonstrated the nature of cellular remodeling occurring in the human colon in inflammation revealing trajectories of differentiation, the connectedness of different cell states together with describing novel epithelial, mesenchymal, T, B and myeloid cell states that hallmark disease. In this work we will build on these findings to explore functional pathways and barrier cell relationships revealed by this analysis that maintain commensal symbiosis in health but lead to breakdown in tolerance driving inflammation in IBD. Specifically, we will focus on defining how the colonic epithelia remodels to lose cell intrinsic barrier protective function, how the supporting mesenchyme fuels inflammation and how heterogenous colonic myeloid cells handle commensal bacteria in health and IBD to drive aberrant adaptive responses.

Amount: £2,097,551
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural basis of use of ion flow across the bacterial inner membrane to power secretion and motility 03 Dec 2019

Bacteria need to control import/export of charged molecules across their relatively impermeable membrane(s) which also house many nano-machines critical for motility and hence infection. These processes are often driven by harvesting the energy stored in ion gradients across the inner-membrane by ion flow through inner-membrane resident channels. Unpublished work from my group has demonstrated that bacterial inner-membrane ion channels which couple ion flow to protein secretion, nutrient import and bacterial motility unexpectedly share a common architecture within their membrane domains. The architecture revealed unexpectedly suggests rotation between components may be mechanistically important and this application seeks to test this hypothesis. The question will be assessed by a series of structural and mechanistic studies that will seek to determine what commonalities in mechanism underlie this shared architecture and how this is adapted to perform the very different biologies achieved. Specifically, what adaptations allow coupling of uni-directional ion flow to achieve work on both sides of the inner-membrane. Using structural and functional tools developed in my group we will study the ion channels in more native contexts both in terms of the membrane bilayer and in terms of the protein interactions that couple ion flow to work to tease out molecular mechanisms.

Amount: £2,286,425
Funder: The Wellcome Trust
Recipient: University of Oxford

Selfish selection of de novo mutations in the male germline 03 Dec 2019

Understanding the factors determining the occurrence of de novo mutations (DNMs) in the human genome is central to genetic disease and genome biology. DNMs arise predominantly in the male germline and increase in frequency with paternal-age. Despite the fact that germline mutation rates are intimately linked to spermatogenesis, very little is known about testicular homeostasis in humans. This proposal aims to address this gap in knowledge by focusing on a new disease-mechanism whereby pathogenic DNMs are preferentially transmitted because they hijack the mechanisms controlling spermatogenesis. This selfish selection process relies on principles similar to oncogenesis to explain why some paternally-derived mutations occur spontaneously up to 1000-fold more frequently than background. Exploiting our current knowledge of selfish selection, this proposal will deploy novel methodologies to describe mutations/genes/pathways subject to this phenomenon, including (1) cataloguing DNMs at single-seminiferous tubule resolution, in geographically-mapped testicular biopsies and in sperm; (2) modelling clonal DNM distribution in tubules to describe spermatogonial dynamics; (3) mining large DNM databases from family trios to detect mutational enrichment. We will also investigate 'selfish mitotic drive', a novel mechanism of mutation enrichment. Together these approaches will allow us to assess the significance of selfish selection for human disease and genome evolution.

Amount: £1,439,158
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining RNA polymerase II transcription units across the mammalian genome 03 Dec 2019

We will define the extent of RNA polymerase II (Pol II) transcription units (TUs) across mammalian genomes, both protein coding (pc) and long noncoding (lnc). For each TU class, termination sites and mechanisms will be scrutinised, especially by definition of XRN2 "torpedo" entry sites at positions of co-transcriptional endonuclease cleavage. Multiple endonucleases will be investigated including CPSF-73, Drosha and Integrator-S11. For lncRNA their mechanism of transcriptional initiation will also be investigated, especially R-loop dependant promoters. Pilot experiments show that R-loops promote antisense lncRNA particularly at pc-gene promoters and enhancers, so defining a new class of Pol II promoter that we intend to fully characterise at a molecular level. Histone genes represent an unusual, ubiquitous Pol II pc-gene class. We will also characterise the termination mechanism for these genes and in particular the role of the novel endonuclease MBLAC1. Finally, we will study the particular case of the H2AX gene that employs both a histone like, poly(A)- termination mechanism as well as a poly(A)+ mechanism. Overall, we will characterise mechanisms that define gene TUs across mammalian genomes to better inform gene function in the rapidly expanding repertoire of genomic sequences being generated for normal and pathogenic human cells.

Amount: £2,400,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Identifying the genetic determinants of Fusobacterium associated with diarrhoeal disease and colorectal cancer in Vietnam 19 Nov 2019

The gut microbiome and its dysbiosis play a central role in understanding infectious and non-infectious conditions. Evidence suggests Fusobacterium nucleatum, an oral anaerobic bacterial pathobiont, potentiates colonic tumourigenesis. My recent work in Vietnam indicates that Fusobacterium, including F. nucleatum, is also enriched in the gut microbiome of children during infectious diarrhoea. My aim is to define the role of Fusobacterium in the resolution of infectious diarrhoea and the development of colorectal cancer, through integrating 16S rRNA-based metagenomics in two distinct clinical studies in Vietnam. I will examine the impact of Fusobacterium gastrointestinal overgrowth and microbiome dysbiosis on diarrhoeal duration in children. Additionally, I will measure the prevalence and distribution of F. nucleatum in the microbiomes of gut mucosa taken from colorectal cancer patients. I will perform whole genome sequencing on the F. nucleatum isolated from collected saliva, diarrhoea stools, and colonic tumour mucosa. Using genomics and phylogenetic analyses, I aim to identify genetic factors associated with F. nucleatum colonization in different human body compartments (oral, colonic) and pathological states (tumour, non-tumour). These findings will enable future in-depth studies, contributing to the development of non-invasive diagnostic marker for colorectal cancer and targeted Fusobacterium therapies in these two diseases.

Amount: £223,772
Funder: The Wellcome Trust
Recipient: University of Oxford

Material classification by man and machine: Understanding human perception using psychophysics and convolutional neural networks 06 Nov 2019

The primary focus is to uncover computational mechanisms underlying material perception, with particular emphasis on "perceptual constancy" – the stability of judgements about objects in the world, despite changes in the proximal stimulus. My approach to this problem is to capitalise on recently developed deep-learning paradigms by evaluating and interpreting activation maps of convolutional neural networks (CNNs) that have been trained to replicate human performance in classifying material properties, such as colour, gloss and translucency, and to use these to identify candidate models of human perception. The key stages are to (i) generate computer-rendered training images with diagnostic conditions of lighting, viewpoint and material parameters; (ii) obtain human perceptual labels for 15,000 images using online methods, validated with lab-based measurement; (iii) train CNNs with either ground-truth or human labels; (iv) interpret the CNNs using visualisation tools; and (v) run psychophysical tests of CNN-inspired models of human vision. The goal is to learn about mechanisms of human material perception by decoding the internal structures of these networks and comparing their behavioural responses to new images. Cue-perturbation methods will be used to test the importance of the recovered features for human perception. Perceptually labelled images will be additionally analysed with traditional methods.

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Oxford