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Recipients:
Broadfield Primary School
University of Oxford
Amounts:
£0 - £500
£500 - £1,000
Award Year:
2017

Results

Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach 01 Oct 2017

Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions. The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Using two different approaches small molecules have been identified that bind to RAS at the same point of contact as the anti-RAS VH. The Seeding Drug Discovery Award will be used to develop these hits through to leads and ultimately the identification of a preclinical development candidate.

Amount: £98,762
Funder: The Wellcome Trust
Recipient: University of Oxford

Discretionary Award 30 Sep 2017

<p>'Sacred Water' &ndash; an engagement project run by artist Lena Bui, was a creative space for researchers at OUCRU-Nepal and people living in the Kathmandu Valley to discuss health with a focus on water.&nbsp; However, the earthquake of 2015 caused many participants to reflect&nbsp;on a wider view of health. Lena became interested in what people turn to for a sense of wellbeing&nbsp;- cultural rituals, western medicine, traditional healers, astrologers, or god.&nbsp; She developed a script based on personal accounts and will now continue the collaboration with OUCRU-NP and the local community to develop the project into an exhibition with a feature-length film as an exploration of health beyond the functioning of a physical body. &nbsp;</p> <p>The film, <em>A Vertical Walk, </em>is a mixture of documentary, travelogue, essay video and experimental images, taking the viewers&nbsp;through landscapes shaped by accounts and fragments of dreams and memories. A public exhibition, held in Kathmandu, will consist of the film, animations, larger paintings and open discussions with the artist and researchers. We will collaborate with a local venue to create a space promoting reflection on the essence of resilience and the role of culture and faith in our existence and sense of wellbeing.</p>

Amount: £40,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Vacation Scholarships 2017 - University of Oxford 16 Jun 2017

<p>Vacation Scholarships 2017-University of Oxford</p>

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

Extension of Serial Femtosecond Crystallography (SFX) at the European X-Ray Free Electron Laser (XFEL) 30 Sep 2017

Third generation synchrotron sources have revolutionised our understanding of the macromolecular machinery of the cell - over 33,000 structures have been elucidated in the last five years, providing atomic detail of macromolecular complexes, membrane proteins and viruses. Fourth generation light sources, such as hard X-ray Free Electron Lasers (XFELs) will allow us to greatly improve one of the bottlenecks of Structural Biology by removing the need for large crystals, which is achieved by outrun ning radiation damage. XFELs also enable sub-picosecond time-resolved analyses and may ultimately provide atomic information for single particles such as viruses and large complexes. The UK is currently not committed to or involved in the construction of a fourth generation light source, including the European XFEL, under construction in Hamburg. This proposal aims to enfranchise the UK structural biology community, amongst the leading in Europe, in this potentially game-changing technology. W e propose to provide training and infrastructure and to directly contribute to the construction and operation of SFX, a user facility for serial femtosecond crystallography at XFEL. An UK Hub at Diamond will allow sample preparation and triage to optimise the use of SFX by UK scientists and maximise the impact of XFEL.

Amount: £692,010
Funder: The Wellcome Trust
Recipient: University of Oxford

Neuroscience 30 Sep 2017

Not available

Amount: £2,980,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Cellular Structural Biology 30 Sep 2017

Not available

Amount: £2,460,000
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £2,228,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Assessing the effect of the Xrn1 exoribonuclease on global and specific rates of protein synthesis 27 Apr 2017

<p>Gene expression is a complex process requiring the coordination of transcription, transcript turnover, translation and proteostasis. When coordinated, these processes can be adapted to allow cells to respond to changes in growth rate and during differentiation. How these processes are coordinated remains a long-standing question. The exoribonuclease Xrn1 is proposed to coordinate transcription and translation via control of steady-state RNA levels and may be part of the mechanism. In this proposal we intend to test one aspect of the proposed model: that Xrn1 regulates steady-state RNA levels and this in turn affects steady-state protein levels. We predict that rates of protein synthesis will change as steady-state RNA levels change and this relationship will be disrupted in cells lacking Xrn1. To assess rates of protein synthesis, we will pulse label cells with puromycin and use a specific antibody to assess the degree of global and specific protein puromycylation in the presence and absence of Xrn1. By assessing rates of protein synthesis for specific proteins we will be able to relate this to levels of protein, transcripts and transcription in the WT and <em>xrn1</em><em>&Delta;</em> strains, obtain preliminary data to validate our hypothesis and if encouraging to support a larger scale analysis.</p>

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

CHIM - Shigella sonnei in Vietnamese adults - Development funds 17 Nov 2017

<p>Diarrhoea remains a major cause of childhood morbidity and mortality globally. The vast majority of the 2 billion<br> annual diarrhoeal infections occur in low and middle-income countries (LMICs). Members of the genus <em>Shigella</em><br> are key agents of diarrhoea in LMICs, and <em>S. sonnei </em>is replacing <em>S. flexneri </em>as the predominant species globally.<br> There is a necessity to improve our knowledge of <em>S. sonnei</em> infections in LMICs, with a specific requirement to<br> better understand host-pathogen interactions and the natural history of disease in a setting where the organism<br> is well understood, well described, and associated with a significant disease burden. Therefore, we aim to<br> establish a Controlled Human Infection Model (CHIM) of <em>S. sonnei</em> diarrhoea in healthy Vietnamese adults.&nbsp;</p> <p>&nbsp;</p> <p>This is an innovative project will be the first CHIM study conducted at the Vietnam MOP.&nbsp; Therefore, it is imperative that the project is carefully designed in consultation with all relevant stakeholders. In order to ensure that the proposal is developed to the required standard in the timeframe available, I am requesting funds to employ an international postdoctoral assistant, with a background in microbiology and clinical research on a consultancy basis.&nbsp;</p>

Amount: £21,120
Funder: The Wellcome Trust
Recipient: University of Oxford

Malaria Controlled Human Infection Model - application development 17 Nov 2017

<p>We wish to apply for funds to develop the malaria CHIM application. These are for a Co-investigators/stakeholders meeting to be held in Bangkok, Thailand, on 30<sup>th</sup> and 31<sup>st</sup> January 2018 and to support a writing meeting of the PIs in February 2018 in Kilifi, Kenya.</p>

Amount: £22,186
Funder: The Wellcome Trust
Recipient: University of Oxford

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

<p>Following a positive response to the&nbsp;preliminary submission for grant funding&nbsp;to&nbsp;establish a Dengue Controlled Human Infection Model (Dengue-CHIM )&nbsp;in Ho Chi Minh City, Vietnam, I am submitting this request&nbsp;for a small grant&nbsp;to assist in refining and&nbsp;developing the main proposal prior to&nbsp;final&nbsp;submission in March 2018.</p> <p>&nbsp;</p> <p>During this pre-submission phase I plan to employ an experienced&nbsp;post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the&nbsp;current understanding of the immune response to/protection from&nbsp;DENV infection and disease, particularly focusing on&nbsp;immune correlates of protection.&nbsp;</p> <p>&nbsp;</p> <p>This will be the first application of a Dengue-CHIM approach in any dengue&nbsp;endemic setting, and&nbsp;raises a number of important bioethical&nbsp;concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months&nbsp;to engage with&nbsp;key Vietnamese stakeholders to discuss the important issues surrounding endemic setting&nbsp;CHIMs,&nbsp;conduct preliminary informal interviews with these individuals, and help to develop the agenda for&nbsp;a 2 day &nbsp;workshop&nbsp;focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.<br> &nbsp;&nbsp;</p> <p>&nbsp;</p> <p>&nbsp;</p>

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

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

<p>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 &lsquo;pathfinder&rsquo; topic &ndash; 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.</p> <p>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 &lsquo;science&rsquo; of community engagement and outline a clear value proposition for CE in global health research (14).</p>

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

Overcoming contraceptive discontinuation by overcoming side-effects: paving the way for personalized contraception in Ethiopia 04 Dec 2017

<p>In the developing world, millions of women discontinue hormonal contraception due to the experience of debilitating physiological side-effects (e.g. excessive and irregular bleeding), yet the causes of these adverse effects is not known. This project will be the first to test the hypothesis that side-effects are caused by unnecessarily high dosage of exogenous hormones in hormonal contraceptives (e.g. injectables) compared with women&rsquo;s endogenous hormones, with the aims of accumulating primary evidence for optimizing contraception to communities and individuals. The research will focus on the use of injectables in Ethiopia, where unmet needs for contraception reach the highest levels in Africa. The PI will build on both an interdisciplinary team of researchers in anthropology, population health, epidemiology, microbiology and medicine and a long-term collaboration with the Institute of Development and Policy Research of Addis Ababa University to implement and run the project. The findings will act as a stepping stone to both engage pharmaceuticals and scale-up the research to produce a statistical model for delivering contraception, predicting, given a woman&rsquo;s context, the range of contraceptive doses minimizing side-effects whilst still suppressing ovulation. This predictive model will be taken to stakeholders worldwide to stimulate transformational innovations for designing and delivering variable-dose contraceptives.</p>

Amount: £97,126
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding and engineering complex microbial communities 28 Nov 2017

<p>The human microbiota provides protection against pathogens via colonisation resistance. However, this resistance is not guaranteed, especially in the face of antibiotic treatment that suppresses the microbiota. My goal is to engineer communities for robustness to both antibiotics and pathogens. The challenge is that communities are complex systems&nbsp;containing many interacting and evolving species, making them challenging to predict and understand.&nbsp;</p> <p>&nbsp;</p> <p><em>Aim 1</em><em>. Develop theory and analysis tools for complex microbial communities</em></p> <p>We will develop complex systems theory and quantitative tools to meet the challenges of understanding and engineering diverse communities.&nbsp;</p> <p>&nbsp;</p> <p><em>Aim 2</em><em>. Apply theory to </em>in-vitro <em>gut communities</em></p> <p>We will apply our theory and test our ability to design gut communities that are robust to either antibiotic treatment, colonisation by the enteric pathogen <em>Salmonella</em> Typhimurium, or both. We will then study community and pathogen evolution: can a pathogen easily resist a probiotic community?&nbsp;Will the community evolve in response?&nbsp;</p> <p>&nbsp;</p> <p><em>Aim&nbsp;</em><em>3</em><em>. Apply theory to S. </em>Typhimurium <em>pathogenesis</em></p> <p>We will study <em>S</em>. Typhimurium in gnotobiotic mice and test our ability to design robust communities <em>in vivo</em>. We will ask if&nbsp;<em>S</em>. Typhimurium&nbsp;can overcome <em>in vivo </em>colonisation resistance.</p>

Amount: £1,851,465
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular control of pathogenic neutrophil responses in inflammation 28 Nov 2017

<p>Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.</p>

Amount: £1,541,677
Funder: The Wellcome Trust
Recipient: University of Oxford

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

<p>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&nbsp;<em>pros/prox1, </em>the regulator of NSC proliferation and differentiation and <em>myc, </em>the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of <em>pros</em>, <em>myc</em> and 21 additional functionally important examples we have discovered, all of which have extremely long 3&rsquo;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.</p>

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

Understanding the link between CpG islands and gene transcription 28 Nov 2017

<p>CpG islands(CGIs) are epigenetically specified elements that are intimately associated with over two-thirds of human gene promotors, yet whether CGIs regulate gene expression has remained enigmatic. This gap in our understanding of gene promoter function has serious implications for human health given that CGIs are perturbed in cancer and other debilitating human diseases. We have recently discovered that CGIs are recognized by reader proteins which can regulate gene expression. Capitalising on these advances, I will now discover how CGIs and the proteins that read them control the transcriptional machinery at gene promoters. I will achieve this transformative new mechanistic understanding through a multidisciplinary and hypothesis-driven programme of research that builds on a series of exciting new and unpublished observations to discover how CGIs function to activate<em><strong>(Aim1)</strong></em> and maintain<em><strong>(Aim2)</strong></em> transcription, and test whether CGIs create gene expression switches<em><strong>(Aim3)</strong></em>. These new discoveries will help to redefine our understanding of how gene promoters function to control gene expression and will provide the basis on which new therapeutic interventions can be developed for diseases where normal CGI biology is perturbed.&nbsp; &nbsp;&nbsp;</p>

Amount: £2,072,282
Funder: The Wellcome Trust
Recipient: University of Oxford

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

<p>The mechanisms facilitating &nbsp;the assembly of <strong>Human cytomegalovirus (HCMV)</strong> in the cytoplasm of infected cells, a complex process termed <strong>&lsquo;secondary envelopment&rsquo;</strong>, 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 &lsquo;lifecycle&rsquo;. 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 <strong>novel approach</strong> that separates these <strong>intermediates in time and space</strong>. 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:</p> <p>&nbsp;</p> <p>-Identify key players in tegument assembly on capsids/membranes.</p> <p>-Elucidate the order and spatial organisation of tegument assembly.</p> <p>-Validate the interactions in vivo and analyse capsid tegumentation in vitro.</p> <p>-Integrate the information into a spatiotemporal model.</p> <p>&nbsp;</p> <p>This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.</p>

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