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Recipients:
Broadfield Primary School
University of Oxford
Amounts:
£500 - £1,000
£10,000,000+
Award Year:
2018

Results

Structural studies of the host-parasite interactions at the heart of malaria pathogenicity 05 Apr 2018

<p>Our proposed activities consist of two major strands.</p> <p>&nbsp;</p> <p>Firstly we wish to take our research on tour, developing a high quality interactive stall which will allow us to present our findings to those who visit science fairs. We have secured a place at the Royal Society Summer Science Exhibition in July 2018, as the first outing for our display and this provides the deadline by which we must have the stall in place. As this is one of the UK&rsquo;s premier science festival, visited by ~13,000 people each year, this is a great opportunity to meet people and to share our research. We will also ensure that our stand is fully updateable in content &ndash; for example using interactive screens which can be altered over time. We will next present at the Oxford Science Festival in 2019 and 2020, at which the Biochemistry Department has committed space. We will also apply to present at another major science festival as soon as applications open (i.e. Cheltenham and Edinburgh) in each of 2019 and 2020.</p> <p>&nbsp;</p> <p>This will be supported by digital content, including a ~2 minute video&nbsp;which will describe our approach towards rational malaria vaccine design and will be posted on Youtube. We will also develop an interactive vaccine game in which players can allocate health budgets and see the effect on malaria prevalence. Together with informative content about our research, these will widen the accessibility of our research.</p>

Amount: £49,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Becoming Good: Early Intervention and Moral Development in Child Psychiatry 10 Jul 2018

<p>Young people are increasingly targets of interventions in mental health, using predictive and preventive tools emerging from genetics, neuroscience, digital technology and big data. Such innovations may well do good, but they also carry significant ethical challenges. <strong>We will develop a scalable digital solution to educate, engage and empower young people in reflection on these challenges and in decision-making.</strong></p> <p>&nbsp;</p> <p><strong>Outputs:</strong></p> <p>&nbsp;</p> <ul> <li>International consultation to identify young people&rsquo;s needs, values and preferences regarding mental health innovations <ul> <li>Expected reach: 2,000</li> </ul> </li> <li>White paper for policy-makers based on consultation <ul> <li>Leveraging our relationships with e.g. WHO, UK POST, UN and UK Government: https://www.gov.uk/government/publications/a-framework-for-mental-health-research.</li> </ul> </li> <li>Validated game prototype as a digital bioethics solution <ul> <li>Develop, test and iterate the prototype, <strong>working in partnership with young people at every stage</strong></li> <li>Reach (aim: 1000&nbsp;users in validation stages; approx 10,000 if game is appropriate to distribute at scale)</li> </ul> </li> <li>Global group of young leaders to co-lead development, testing and iteration;&nbsp;inform research direction and focus&nbsp;(aim: 40 young leaders; 15 countries) <ul> <li>Leveraging our networks: YPAGs, NIHR GenR, ICAN (international YPAGs); NCD Child; Youth Ambassadors in&nbsp;dissemination campaign for Lancet Commission on Global Mental Health (led by BeGOOD)</li> </ul> </li> <li>Collaboration with OxInnovation to evaluate game potential in UK education and health contexts &nbsp;</li> <li>Enrichment programme evaluation</li> </ul> <p>&nbsp;</p> <p><strong>Outcomes:</strong></p> <ul> <li><strong>Educate, engage and empower young people in the context of ethics in mental health interventions </strong></li> <li>Increase societal awareness of young people&rsquo;s capacity and importance of young people's voices in healthcare decision-making</li> <li>Build sustainable PE capacity in our team</li> <li>Illustrate the limits and potential of a digital bioethics tool</li> </ul>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research 05 Apr 2018

<p>As REACH enters its second year, we have an exciting opportunity to use our early findings and to expand our use of visual methods to spark wider community and public debate about the ethical issues arising in research with women, children&nbsp;and their families in contexts of poverty and gender inequality. This proposal complements existing Africa and Asia Programme provisions for public engagement at the KEMRI-Wellcome Trust Research Programme, Africa Health Research Institute and the Mahidol Oxford Tropical Medicine Research Unit.</p> <p>&nbsp;</p> <p>We propose a linked&nbsp;series of public engagement workshops and events across our four study countries, to engage with members of the general public, community activists, humanitarian health workers, programme leaders in women&rsquo;s and children&rsquo;s health, and community advisory boards. Using cases and videos to prompt lively debate and discussion, we hope to learn from participants about what ethical research means to them, what vulnerability and&nbsp;empowerment mean to them,&nbsp;potential concerns about research, and ideas for responding to these concerns. Participatory workshops&nbsp;will be filmed and an edited video created to share public insights with researchers, universities, funders, ethics committees, and other stakeholders in global health.</p> <p>&nbsp;</p> <p>These activities will:</p> <ol> <li>Offer an opportunity for public stakeholders to shape the debate around research ethics in their communities and beyond.</li> <li>Increase public awareness and elicit public insights about the role for ethical research in evidence-based responses to health and social needs in contexts of poverty and gender inequality.</li> <li>Offer public engagement training and practice for developing country researchers in research ethics.</li> </ol>

Amount: £140,079
Funder: The Wellcome Trust
Recipient: University of Oxford

open access award 2017/18 30 Sep 2018

Not available

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

open access award 2017/18 30 Sep 2018

Not available

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Epigenetic mapping of immune cells in colorectal cancer 24 Apr 2018

<p>A recent large-scale study of 39 different types of cancers has shown that the expression of the gene <em>KLRB1</em>, encoding the protein CD161, was the top predictor of favourable prognosis and overall survival. CD161 is expressed on various immune cells, including newly discovered populations such as MAIT cells and innate lymphoid cells. To identify the intratumoural cells contributing to improved prognosis, I will develop a tool for the bioinformatic enumeration of pure cell types from complex populations. As chromatin accessibility and enhancer landscape reflects cell identify better than mRNA levels, differentially accessible loci will be a unique signature for each cell type. Using state-of-the-art technologies, my key goals are to:</p> <p>&nbsp;</p> <ol> <li><strong>Generate a comprehensive epigenetic signature matrix encompassing novel immune cell types</strong></li> <li><strong>Use this to deconvolute the epigenome of colorectal carcinoma tumours</strong></li> <li><strong>Directly identify the infiltrating CD161-expressing population correlated with improved survival in colorectal cancer</strong></li> </ol> <p>&nbsp;</p> <p>By improving our understanding of how multiple immune populations collectively infiltrate tumours, including novel CD161-expressing cells, this work will enable future cancer immunotherapies to target protective immune subsets. Furthermore, the proposed work will provide a resource that can be easily applied to epigenetic data from other malignancies.</p>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Medicine Quality and Public Health Conference 2018 30 Sep 2018

<p>Globally, medicine regulatory authorities, research groups, international organisations, law enforcement agencies and other key stakeholders, including the pharmaceutical industry, are trying to keep patients safe and ensure that the benefits of modern medicine are delivered to patients. However, organisations working in this field tend to be fragmented with the wide diversity of professionals required to tackle this important issue, from chemists to lawyers, rarely discussing solutions together. Indeed, there has never been an opportunity for the diverse stakeholders involved in medicine quality and drug regulation to come together &ndash; within the framework of a specific academic conference &ndash; to share ideas and expertise, and to outline the coordinated steps that need to be taken to tackle the problem on an international scale. Drawing on the achievements of our successful, annual, multidisciplinary course on the Quality of Medical Products &amp; Public Health at the London School of Hygiene &amp; Tropical Medicine and Boston University, we are organising the first-ever dedicated academic and programmatic conference on Medicine Quality and Public Health.</p> <p>Wellcome is supporting the attendance of 10 participants from LMICs.</p>

Amount: £24,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Translation Partnership Award (iTPA): Thailand Major Overseas Programme 30 Sep 2018

The team at MORU will focus on closing the gap between research and implementing interventions, building capacity and expertise to support early translation to improve the health of people in low-income countries.

Amount: £988,404
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding unconventional kinetoplastid kinetochores in Trypanosoma brucei 10 Apr 2018

<p>I am interested in understanding the mechanism of how eukaryotic cells inherit their genetic material at each round of cell division. I have been studying the kinetochore, the macromolecular protein complex that drives chromosome segregation. Although it was widely believed that the structural core of kinetochores would be composed of proteins that are conserved in all eukaryotes, I discovered an unconventional class of kinetochore proteins (KKT1&ndash;20) in <em>Trypanosoma brucei</em>, an evolutionarily-divergent kinetoplastid parasite. My current goal is to understand how they carry out conserved kinetochore functions such as binding to DNA and&nbsp;microtubules. Based on preliminary data, I propose that two homologous protein kinases KKT2 and KKT3 lie at the base of the kinetoplastid kinetochore. I will aim to understand how these proteins localize specifically at the centromeric DNA using a variety of approaches. I will also characterize the KKT4 protein to reveal the mechanism of microtubule interaction. To understand the design principle of kinetoplastid kinetochores, I will reconstitute and characterize kinetochore subcomplexes. Finally, I will examine how the&nbsp;evolutionarily-conserved Aurora B kinase regulates the function of unconventional kinetoplastid kinetochores.</p>

Amount: £1,890,493
Funder: The Wellcome Trust
Recipient: University of Oxford

Serine ADP-ribosylation in genome stability and human disease 10 Apr 2018

<p>ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr.&nbsp; Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.</p>

Amount: £2,074,702
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanisms of DNA interstrand crosslink repair in humans. 10 Apr 2018

<p>My research is focused on uncovering the molecular mechanisms of DNA interstrand crosslink&nbsp;(ICL) repair in humans. Disruption of the underlying DNA-repair pathway causes Fanconi Anemia&nbsp;(FA), with serious cancer susceptibility. Also, ICL-forming drugs are used&nbsp;therapeutically in non-FA cancer patients, however resistance is a major problem. Targeting the&nbsp;FA-pathway could allow clinicians to treat these patients.</p> <p>&nbsp;</p> <p>A key and fundamental event in the FA-pathway is the recruitment of repair proteins to ICLs. Specific and timely recruitment is essential for accurate repair. We have recently&nbsp;discovered proteins specifically detecting ICLs and&nbsp;we have obtained the cryo-EM structure&nbsp;of&nbsp;other ICL-repair proteins.</p> <p>&nbsp;</p> <p>My aim over the next five years is to advance the field further by uncovering mechanistically how&nbsp;repair factors&nbsp;are activated and&nbsp;recruited to ICLs&nbsp;at the single-molecule level.</p> <p>&nbsp;</p> <p>We will:</p> <p>&nbsp;</p> <p>1) Dissect the mechanism of initial recruitment of repair factors to ICLs.<br> 2) Uncover functions of identified proteins in FANCD2-complexes in ICL-repair.<br> 3) Determine roles of novel phosphorylation sites on FANCD2/FANCI.<br> 4) Elucidate mechanism of FANCD2/FANCI activation.</p> <p>&nbsp;</p> <p>&nbsp;</p> <p>Addressing these central questions will not only greatly advance our understanding of ICL-repair,&nbsp;but will also likely enhance our understanding of other DNA repair pathways utilizing analogous&nbsp;mechanisms.</p>

Amount: £1,573,740
Funder: The Wellcome Trust
Recipient: University of Oxford

Beyond the pol II CTD: the expanding roles of the pol II CTD modification enzymes 10 Apr 2018

<p>The multiple Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 repeats within the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (pol II) undergo reversible phosphorylation during transcription of human protein-coding genes<sup>1</sup>. The pattern of CTD phosphorylation is controlled by CTD kinases and phosphatases through the transcription cycle, which ensures the sequential recruitment of transcription and RNA processing factors required for correct gene expression.</p> <p>It is now becoming clear that the &quot;CTD&quot; modification enzymes have multiple additional targets that may play key roles in transcription, RNA processing and even translation. The exact roles that these kinases and phosphatases play in the cell is therefore not yet well understood. The aim of the proposed research is to understand the precise role(s) that CTD kinases and phosphatases play in transcription and downstream processes through modification of the CTD and other factors, what molecular mechanisms are involved and how their activities are co-ordinated. Towards this goal, I will use state of the art technology to determine the direct effect of loss of CTD kinase or CTD phosphatase activity, identify the targets of the CTD kinases and phosphatases and characterize the molecular interactions underlying the functions of CTD kinases and phosphatases.</p>

Amount: £1,312,233
Funder: The Wellcome Trust
Recipient: University of Oxford

Determining the mechanisms underlying epigenetic inheritance of chromosome structure and gene expression states 10 Apr 2018

<p>Gene expression states and chromosome structure can be stably perpetuated across cell division cycles in a manner that is uncoupled from direct genetic instructions. I aim to understand how chromatin can self-duplicate and be inherited. Defining the mechanisms by which chromatin components are instructive in maintaining memory is fundamental to our understanding of genome stability and cellular differentiation. In the first two aims, I focus on the mammalian centromere which is an excellent model for self-templating epigenetically-inherited chromatin, based on the histone H3 variant CENP-A. I will ask two fundamental questions: i) how can centromeric chromatin be initiated <em>de novo</em>? ii) how is it subsequently stably inherited? In the final aim, I will use my expertise in centromere biology to ask how heritable chromatin contributes to the mitotic transmission of active gene expression. I will employ a unique, interferon-inducible&nbsp;gene expression model that results in long-lasting memory of prior induction. I will discover how local chromatin structure cooperates with the transcriptional machinery to ensure robust, long-term maintenance of active transcription and determine its importance for innate immunity. Combined, our discoveries will define the molecular basis and role of chromatin inheritance in the maintenance of cell identity and genome architecture.</p>

Amount: £1,800,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors 10 Apr 2018

<p>We have recently projected that the human bHLH-PAS proteins form a class of transcription factors with great therapeutic promise, and propose to subject this family to in-depth chemical and functional explorations. The sixteen members of this family are functionally non-redundant and have genetic links to cancers, metabolic syndromes, inflammatory diseases, and psychiatric conditions. They share common architectural features that include a conserved DNA-binding domain and dual PAS domains.</p> <p>&nbsp;</p> <p>Our specific aims are:</p> <p>&nbsp;</p> <p>1.&nbsp; Identify chemical ligands for members of the human bHLH-PAS family.</p> <p>&nbsp;</p> <p>2.&nbsp; Determine the ligand-dependent genomic signatures and cellular pathways governed by&nbsp;family members.</p> <p>&nbsp;</p> <p>3.&nbsp; Probe the mechanisms by which chemical ligands manifest their activities through this family.</p> <p>&nbsp;</p> <p>These studies allow us to transition from having visualized their ligand binding properties to employing chemical tools for interrogating and manipulating their functional activities as transcription factors.</p>

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

Accessing the Druggable Genetic Programs Governed by Mammalian bHLH-PAS Transcription Factors 10 Apr 2018

<p>We have recently projected that the human bHLH-PAS proteins form a class of transcription factors with great therapeutic promise, and propose to subject this family to in-depth chemical and functional explorations. The sixteen members of this family are functionally non-redundant and have genetic links to cancers, metabolic syndromes, inflammatory diseases, and psychiatric conditions. They share common architectural features that include a conserved DNA-binding domain and dual PAS domains.</p> <p>&nbsp;</p> <p>Our specific aims are:</p> <p>&nbsp;</p> <p>1.&nbsp; Identify chemical ligands for members of the human bHLH-PAS family.</p> <p>&nbsp;</p> <p>2.&nbsp; Determine the ligand-dependent genomic signatures and cellular pathways governed by&nbsp;family members.</p> <p>&nbsp;</p> <p>3.&nbsp; Probe the mechanisms by which chemical ligands manifest their activities through this family.</p> <p>&nbsp;</p> <p>These studies allow us to transition from having visualized their ligand binding properties to employing chemical tools for interrogating and manipulating their functional activities as transcription factors.</p>

Amount: £2,161,828
Funder: The Wellcome Trust
Recipient: University of Oxford

Metabolic Characterization of Natural Killer T Cell responses to sterile, hypoxic injury 24 Apr 2018

<p>It has been described that&nbsp;ischemia-reperfusion injury (IRI), such as during&nbsp;organ transplantation,&nbsp;evokes damaging sterile inflammation and secondary tissue injury that is&nbsp;dependent on iNKT cell activation, but the underlying mechanisms remain elusive.&nbsp;Similarly, in sickle cell disease (SCD)&nbsp;mice,&nbsp;RBC sickling and widely disseminated microvascular ischemia&nbsp;can be triggered by hypoxia/reperfusion (H/R), presenting a&nbsp;global and scalable model of sterile, NKT-mediated inflammation. We propose here to use state-of-the-art metabolic methodologies to investigate the&nbsp;response to hypoxia and reperfusion (H/R), which ultimately causes NKT cell activation and tissue damage in SCD. Mice carrying the human sickle cell alleles are available and were crossed with NKT-deficient Ja18 mice, thus generating our&nbsp;novel&nbsp;Sickle-Ja18 mouse model which&nbsp;exhibits reduced tissue damage in response to H/R. Together with in-vitro co-culture experiments, we will explore (1)&nbsp;the intrinsic and (2) APC-mediated mechanisms of sterile inflammation caused by hypoxia and reperfusion in the context of sickle cell disease with the ultimate goal to identify&nbsp;metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis. We anticipate that this research will increase our understanding not only of SCD, but also the pathology of IRI, organ transplantation and sterile inflammation.</p>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Flexible task representations for intelligent behavior 24 Apr 2018

<p>A long research tradition in cognitive neuroscience has investigated the role of the prefrontal cortex (PFC) in flexible goal-directed behaviour. This work has yielded important insights, e.g., that the PFC&rsquo;s coding properties flexibly adapt when task demands change&nbsp;to prioritise goal-relevant information. However,&nbsp;it relies primarily upon the use&nbsp;of familiar and explicitly instructed tasks&nbsp;that provide poor fit to&nbsp;human behaviour in naturalistic and open-ended environments, and likely miss&nbsp;essential aspects PFC function. I therefore propose to study the representations that form within PFC as humans learn to perform complex categorisation tasks with only minimal external instruction. I hypothesise that during learning the PFC will form abstract representations of the task&rsquo;s latent structure, that support not only performance in the given task, but also provide provides a scaffold for learning in similar environments. Using representational similarity analyses, in combination with multiple brain recording techniques (fMRI, MEG, ECoG), I will measure how stimulus-evoked neural responses change adaptively during learning, and test if these changes generalise to novel task environments with similar structure. These findings will provide important new insights about the coding mechanisms by which PFC supports flexible behaviour in complex, naturalistic environments.</p>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice 24 Apr 2018

<p>The recent Deciphering Developmental Disorders Study found that mutations in genes encoding epigenetics proteins are a primary cause of intellectual disability. These disorders are incurable and their underlying mechanisms remain elusive. Intriguingly, varying symptom severity has been described in patients with the same causative mutations for a number of these disorders and phenotypes displayed in some mouse models are strain-dependent. To search for secondary mutations that suppress phenotypes in mouse models of the neurological disorder, Rett syndrome, Monica Justice&rsquo;s lab performed a genome-wide screen by inducing random mutations with the chemical mutagen ENU. I aim to take advantage of recent advances in CRISPR/Cas9 technology to develop a CRISPR-based screening method. This method will simplify isolation of modifying mutations, greatly reduce the number of animals required and can be adapted for recessive screening. I will use this method to screen for suppressors of two neurological disorders that are predicted to be modifiable: ATR-X and ADNP syndromes. Both causative genes encode epigenetic proteins: ATRX is a chromatin remodelling ATPase and ADNP is a putative transcription factor. I hope that the &lsquo;hits&rsquo; obtained in these screens will help us to better understand ATRX/ADNP protein function and open up therapeutic avenues for patients.</p>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining the innate-like mucosal T cell response to bacterial infection in airways disease 30 Sep 2018

<p>Exacerbations cause most morbidity, mortality and economic costs of asthma. Most are driven by infections and constitute a significant unmet clinical need, particularly in non-eosinophilic disease. The 2017 AMAZES trial showed azithromycin reduced exacerbations in severe asthma, but raises several critical questions, especially, the relevant mechanisms of action, whether anti-microbial, anti-inflammatory or immunomodulatory, remain unknown.</p> <p>&nbsp;</p> <p>AIMS</p> <p>1.To discover the mechanisms of macrolide activity in neutrophilic asthma.</p> <p>2.To define how non-typeable <em>Haemophilus influenzae</em> (NTHi) establishes a niche in neutrophilic airways.</p> <p>3.To explore the role of mucosal associated invariant T (MAIT) cells and their ligands in infection and asthma.</p> <p>&nbsp;</p> <p>OBJECTIVES</p> <p>1.<em>In vitro</em> modelling of bacteria/epithelial/immune cell interactions in NTHi-infected human airway epithelium at air-liquid interface.</p> <p>2.Murine modelling of mucosal immune responses to NTHi and effects of azithromycin on pulmonary inflammation <em>in vivo</em>.</p> <p>3.Characterisation of human airway cellular immunology and microbiology using bronchoscopy before and after azithromycin therapy to</p> <p>confirm the human relevance of these pathways in asthmatics with/without bacterial airway infection.</p> <p>&nbsp;</p> <p>This work will i) elucidate the basic immunology of host-pathogen interactions and MAIT-cell biology; ii) identify mechanisms and biomarkers key to informing and refining future human clinical trials of macrolides in airways diseases; and iii) explore the therapeutic potential of MAIT-cells.</p>

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Oxford