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

Results

The role of 3' UTR variation in the molecular pathogenesis of motor neuron disease 08 Aug 2018

<p>UV cross-linking and immunoprecipitation (CLIP) is a commonly used method to profile endogenous protein-RNA interactions by sequencing RNA fragments that copurify with a selected RNA-binding protein (RBPs). Integrative analysis of available CLIP data is hampered by the lack of a unified CLIP data resource. 27 variants of the method have already been developed, and these have been used in over a hundred labs to produce thousands of data sets for several hundred RBPs in diverse species, from bacteria to human (Lee and Ule, 2018). Moreover, many tools exist for integrative analysis of processed CLIP data, but unfortunately, there is no available data repository that would provide a unified processing of various types of CLIP data produced by different groups.</p> <p>Here, we propose to establish a public repository of all public CLIP data produced in different cell types, tissues and species. Such a resource would empower wet lab biologists to explore processed CLIP data in a user-friendly manner, and to assess if variations between different CLIP protocols produced in different laboratories influence the reproducibility, technical artefacts and other measures of data quality. Moreover, a unified analysis platforms will provide consistently comparable data to bioinformaticians for integrative meta-analyses of all available data from the various groups. This would enhance the capacity of the RNA community to advance our understanding of epitranscriptomics, and of the regulatory mechanisms of protein-RNA complexes that regulate gene expression.</p> <p>Lee, F.C.Y., and Ule, J. (2018). Advances in CLIP Technologies for Studies of Protein-RNA Interactions. Mol. Cell 69, 354&ndash;369.</p>

Amount: £49,995
Funder: The Wellcome Trust
Recipient: University College London

AHRI STRATEGIC CORE AWARD 10 Jul 2018

Our public engagement strategy sets out our plans support our vision for the Africa Health Research Institute to become a premier global science research institute that engages with its public. We have already established Head of Public Engagement and Communications manager as core funded positions. The activities outlined in this enrichment award proposal build from the strategy to enhance our ability to have constructive, interactive, and integrated engagement with local communities (both in uMkhanyakude and Durban) and the broader public in KwaZulu-Natal, South Africa and internationally. Our diverse research populations, and geographical settings (community, hospital, rural, urban) provide an opportunity to identify aspects of engagement which are common to all, yet also the need for bespoke methodological approaches. Public engagement cannot be something `delivered’ by one or two designated staff members: to succeed we will build shared ownership across all staff and all areas of our work. We propose a series of new activities to ensure we maximise the impact and understanding of AHRI, and which enhance the quality of our research. These include staff working groups delivering work packages on a) Societal Value, b) Schools Engagement, c) Research Participant Advocacy, and d) Researcher Training/Capacity Building. We will ensure that by 2021 `public engagement’ is firmly established across all areas of our work. Mindful of the population base of much of our research activity, this programme will significantly enhance the quality of our research, as well as ensuring research impact through engagement with the public and policy makers.

Amount: £699,967
Funder: The Wellcome Trust
Recipient: University College London

Wellcome Centre for Human Neuroimaging 10 Jul 2018

<p>The Research Enrichment fund will enable us to embed public engagement (PE) into our Wellcome Centre research process.&nbsp;If funded, we will have achieved the following at the end of the proposed Research Enrichment programme:</p> <p>(1) &nbsp;Established a cultural change within our Centre where PE is integrated into all of our research programmes, with more researchers doing PE than not.&nbsp;</p> <p>(2) &nbsp;Provided a comprehensive tiered training program, that produces world-leading researchers with the skills and experience to&nbsp;readily engage with wider communities.</p> <p>(3) &nbsp;Delivered at least 8 PE team-led activities per year targeted towards empowering five typically under-represented community groups in neuroscience who will contribute to and influence our science:&nbsp;</p> <ul> <li>Patients with neurological and psychiatric disorders,</li> <li>Disadvantaged students,</li> <li>Ethnic minorities,</li> <li>Artistic communities and</li> <li>Women in Science, Technology, Engineering and Maths (STEM)).</li> </ul> <p>(4) Built sustainable partnerships with UK charities and organisations who lead in PE, such as the Stroke Association and Science Museum,&nbsp;expanding our reach into these substantial networks.&nbsp;</p> <p>(5) Planned a comprehensive PE programme in line with our PE strategy to continue to enrich and develop our engagement programmes in perpetuity.&nbsp;</p> <p>(6) Evaluated the impact of the cultural change, to ensure that the aims of our PE strategy are achieved within our overall vision.&nbsp;</p> <p>(7) Developed and shared our model for integrating PE into the research process at conferences and with other Wellcome Centres across the UK.&nbsp;</p>

Amount: £266,960
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (London Hub) 30 Sep 2018

<p>The London Hub for Urban Health, Sustainability and Equity aims to be the world&rsquo;s foremost transdisciplinary hub for research, training and pubic engagement on urban health. It is founded on two constituent projects &ndash; Complex Urban Systems for Sustainability and Health (CUSSH) and Pathways to Equitable Healthy Cities (PEHC) &ndash; and involves leading London-based institutions and their global network of collaborating institutions. The Hub&rsquo;s principal objective is to integrate and coordinate research and stakeholder engagement that support evidence-based policies aimed at improving population health, health equity and environmental sustainability in cities around the world. The Hub, and its projects, will achieve this objective through comparative studies that involve participatory research and coproduction of knowledge among academic researchers, policy makers and practitioners, and civil society; developing models for prospective policy evaluation and applying these models to data from our partner cities; and training the next generation of research and policy leaders in urban health, while establishing the foundations for sustaining and expanding the Hub beyond the Wellcome funding period. The CUSSH project focuses on how to transform cities to address vital environmental and population health imperatives, and entails partnership with the cities of London, Beijing, Kisumu, Nairobi, Ningbo and Rennes.</p>

Amount: £5,150,000
Funder: The Wellcome Trust
Recipient: University College London

Lancet Countdown: Tracking Progress on Health and Climate Change 30 Sep 2018

<p>Please see the Executive Summary of the attached document for a summary of the proposal.</p> <p>&nbsp;</p>

Amount: £5,528,492
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 30 Sep 2018

<p>&nbsp; &nbsp; Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to na&iuml;ve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different&nbsp;glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.&nbsp;</p>

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 21 Feb 2018

<p>&nbsp; &nbsp; Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to na&iuml;ve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different&nbsp;glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.&nbsp;</p>

Amount: £1,198,593
Funder: The Wellcome Trust
Recipient: University College London

Using social networks to understand and intervene on HIV epidemic spread 21 Feb 2018

<p>Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa.</p> <p>&nbsp;</p> <p>Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.</p>

Amount: £1,244,577
Funder: The Wellcome Trust
Recipient: University College London

Characterising the neural mechanisms of human memory at high resolution 10 Apr 2018

<p>&nbsp;</p> <p>Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time.&nbsp; My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.</p> <p>&nbsp;</p> <p>&nbsp;</p>

Amount: £2,359,757
Funder: The Wellcome Trust
Recipient: University College London

Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies 10 Apr 2018

<p>Background: Over 1,800 autosomal recessive (AR) Mendelian-disease genes have been identified. Missense mutations account for 59% of protein coding region mutations, yet their precise functional effects remain largely uncharacterized.</p> <p>&nbsp;</p> <p>Two important questions in human genetics aim to explain <strong>interindividual variation</strong> in phenotypic severity and <strong>assign pathogenic mechanisms</strong> to different disease phenotypes (including independent phenotypes within the same syndrome). For AR disorders, it is thought that many missense mutations cause protein instability. For these <strong>hypomorphic mutations</strong>, disease phenotypes are defined according to <strong>quantitative genetic threshold effects </strong>within a protein interaction network. &nbsp;</p> <p>&nbsp;</p> <p>Project: We will focus on a subset of <strong>AR ciliopathies</strong> which are strongly enriched for missense mutations, where complete gene knockout is thought to be lethal (see Rationale-below). We will use gene-editing and quantitative protein-protein interaction analyses to systematically compare the phenotypic effects of frameshift (likely knockout/null) and missense mutations.</p> <p>&nbsp;</p> <p>We will test our hypothesis that these missense mutations disrupt only a subset of gene functions/protein interactions, using phenomics algorithms we have developed and unbiased phenotyping in cell lines and mouse models,&nbsp;allowing us to assign pathogenic mechanisms to disease phenotypes.</p> <p>&nbsp;</p> <p>In future, this approach could be extended to the estimated 10-20% of &gt;3,000 Mendelian-disorders enriched for missense mutations.</p>

Amount: £1,706,863
Funder: The Wellcome Trust
Recipient: University College London

Investigating the role of lung Tissue resident memory T-cell in the immunopathology of human TB 10 Apr 2018

<p>This proposal will examine the involvement of lung Tissue resident memory (Trm) T-cells in the human immune response to TB. Using unique access to fresh human lung tissue, we find evidence of non-recirculating T-cells, consistent with a Trm subset. The importance of Trm to pathogen immunity is becoming increasingly apparent and limited data from mice indicates they are highly active against TB. However, nothing is known about their role in humans and this is important because, as Trm do not recirculate, they are missing from TB immunology data generated to date, which comes from blood. Even bronchioalveolar lavage does not accurately describe the Trm response. We know T-cells are crucial for immunity to TB, and our failure to establish T-cell correlates of protection may come from not taking Trm into account. We will use novel tools, including single cell sequencing, Mass Cytometry and multiparimeter fluorescence microscopy to investigate the role of Trm in the TB response in human lung. Then, using a novel 3D-granuloma model we will test this observational data to determine the functional details of protective or harmful T-cell responses. This will establish the T-cell correlates of protection in humans and provide a basis for rational vaccine design.</p>

Amount: £1,864,056
Funder: The Wellcome Trust
Recipient: University College London

Pre-configured and learned properties of hippocampal circuits 10 Apr 2018

<p>Despite recent advances in systems and computational neuroscience, very little is known about how the brain&rsquo;s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this&nbsp;gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether &lsquo;non-place&rsquo; coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (&lsquo;continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.</p>

Amount: £1,097,310
Funder: The Wellcome Trust
Recipient: University College London

Developing novel gene therapy technology for treatment of glycine encephalopathy 15 Sep 2018

"Glycine encephalopathy, also known as non-ketotic hyperglycinaemia (NKH), is a life limiting inherited neuro-metabolic disease which presents soon after birth and leads to severe neurological outcomes including epilepsy and profound developmental delay. Current treatments for NKH are neither effective long-term, nor curative. Glycine encephalopathy is characterized by accumulation of glycine and is known to result from mutation of genes that encode the glycine cleavage system so that glycine cannot be broken down. The majority of affected children carry mutations in GLDC, encoding glycine decarboxylase. In this project we aim to develop gene therapy for glycine encephalopathy to restore GLDC function in the liver using lentiviral vector to provide permanent delivery of the therapeutic sequence. In a glycine encephalopathy model we will test a novellentiviral vector that offers enhanced safety and performance. This will be a key step towards potential clinical implementation of this therapy

Amount: £365,837
Funder: The Wellcome Trust
Recipient: University College London

Politics, medical knowledge and development: from Israel to Ethiopia and Eritrea (and back) 07 Mar 2018

<p>This project will critically study how the circulation of medical knowledge and practices of developing health programs between Israel, Ethiopia and Eritrea, shape regional politics, immigration dynamics and racialization processes in Africa and the Middle East. Specifically, how political instrumentalisation&nbsp;of medical knowledge affects three interrelated dynamics: Constructing&nbsp;health development schemes that facilitated an Israeli&nbsp;strategic foothold in Ethiopia. Establishing a strainer mechanism to sift through the Ethiopian&nbsp;Jews immigrating to Israel and legitimising&nbsp;the detention and potential incarceration of&nbsp;Eritrean asylum seekers upon their arrival to Israel's border with Egypt. The project's principal goals are:</p> <p>&nbsp;</p> <p>1. Conducting <strong>exploratory research</strong> into the medical interactions between Israel, Ethiopia, and Eritrea.</p> <p>&nbsp;</p> <p>2. Developing a <strong>research platform</strong> including an advisory board, research workshop, a panel in an international conference, and a digital archive.</p> <p>&nbsp;</p> <p>3. Consolidating an <strong>academic network</strong> for an intellectual community of leading scholars and early career researchers examining the politics of medical development in the Middle East and Africa.</p> <p>&nbsp;</p> <p>4. Constructing a platform and network as the <strong>first phase</strong> of research exploring the political legacies of medical development and health aid in the Global South.&nbsp;</p>

Amount: £29,330
Funder: The Wellcome Trust
Recipient: University College London

Personalising the pharmacological treatment of bipolar disorder 23 May 2018

<p><strong><u>Background</u></strong></p> <p>Prescribing for bipolar disorder is a major clinical dilemma as long-term pharmacological treatment is often necessary. Lithium is&nbsp;the most effective mood stabiliser. However,&nbsp;only 30% of individuals have a good therapeutic response. Presently, there is no reliable way to predict response or adverse event risk, or if an alternative treatment would be better for that patient.</p> <p>&nbsp;</p> <p><strong><u>Aim</u></strong><br> <strong>To personalise prescribing for people with bipolar disorder via prediction models that quantify potential benefits and risks of existing treatments based on clinical phenotypic characteristics of the individual</strong>.</p> <p>&nbsp;</p> <p><strong><u>Objectives</u></strong></p> <ul> <li>Identify individualised clinical predictors of lithium and second-generation antipsychotic response.</li> <li>Determine clinical predictors of chronic kidney disease&nbsp;in individuals taking lithium.</li> <li>Determine clinical predictors of pathological weight gain in individuals taking second-generation antipsychotics.</li> </ul> <p>&nbsp;</p> <p><strong><u>Methodology</u></strong><br> <strong>Data sources</strong><br> Swedish population registers, Hong-Kong health registers, Taiwanese health insurance database, UK primary care data linked to secondary care admission records, and UK mental health care data.</p> <p>&nbsp;</p> <p><strong>Analyses</strong><br> Traditional epidemiological and machine learning methods; drawing on the strengths of each approach.</p> <p>&nbsp;</p> <p><strong>Prediction model generation</strong><br> I will combine predictors from different datasets; resulting in models predicting drug response, chronic kidney disease and weight gain.</p> <p>&nbsp;</p> <p><strong><u>Application</u></strong><br> Prediction models will be presented as online and smartphone application clinician decision aids.</p>

Amount: £460,704
Funder: The Wellcome Trust
Recipient: University College London

Cellular mechanisms underlying the morphogenetic biomechanics of mammalian neural tube closure 30 Sep 2018

<p>Primary neurulation is a biomechanical process whereby the flat neural plate folds into a closed neural tube (NT). Closure initiates at the hindbrain/cervical boundary and &ldquo;zippers&rdquo; bi-directionally to form the cephalic and spinal NT. Failure of NT closure results in defects including spina bifida, which continue to affect 1:1,000 pregnancies. Despite advances in delineating its genetic control, we lack an integrated understanding of neurulation as a biomechanical morphogenetic process. To this end I have combined mouse posterior neuropore (PNP) live-imaging, laser ablation, and novel strain-mapping workflows to describe the tissue-level biomechanics of spinal closure. These revealed that the PNP is biomechanically coupled by a far-reaching actomyosin network, identified teratogenic/genetic models in which altered PNP biomechanics predict spina bifida, and identified a novel closure-initiation point (&ldquo;Closure 5&rdquo;) which forms at the embryo&rsquo;s caudal extreme. We now propose to determine:</p> <ol> <li>Are mechanical forces which promote and oppose NT closure balanced through actomyosin-dependent contractility overcoming tissue rigidity, up to a failure threshold?</li> <li>Do biomechanical differences between spinal and cephalic closure account for the latter&rsquo;s apparent predisposition to failure?</li> <li>Does Closure 5 formation critically facilitate completion of spinal neural tube closure in humans and mice, and how is its morphogenesis regulated?</li> </ol>

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University College London

Cellular mechanisms underlying the morphogenetic biomechanics of mammalian neural tube closure 23 May 2018

<p>Primary neurulation is a biomechanical process whereby the flat neural plate folds into a closed neural tube (NT). Closure initiates at the hindbrain/cervical boundary and &ldquo;zippers&rdquo; bi-directionally to form the cephalic and spinal NT. Failure of NT closure results in defects including spina bifida, which continue to affect 1:1,000 pregnancies. Despite advances in delineating its genetic control, we lack an integrated understanding of neurulation as a biomechanical morphogenetic process. To this end I have combined mouse posterior neuropore (PNP) live-imaging, laser ablation, and novel strain-mapping workflows to describe the tissue-level biomechanics of spinal closure. These revealed that the PNP is biomechanically coupled by a far-reaching actomyosin network, identified teratogenic/genetic models in which altered PNP biomechanics predict spina bifida, and identified a novel closure-initiation point (&ldquo;Closure 5&rdquo;) which forms at the embryo&rsquo;s caudal extreme. We now propose to determine:</p> <ol> <li>Are mechanical forces which promote and oppose NT closure balanced through actomyosin-dependent contractility overcoming tissue rigidity, up to a failure threshold?</li> <li>Do biomechanical differences between spinal and cephalic closure account for the latter&rsquo;s apparent predisposition to failure?</li> <li>Does Closure 5 formation critically facilitate completion of spinal neural tube closure in humans and mice, and how is its morphogenesis regulated?</li> </ol>

Amount: £1,101,901
Funder: The Wellcome Trust
Recipient: University College London

Mapping the neurocomputational landscape of obsessive-compulsive disorder 06 Jun 2018

<p >Obsessive-compulsive disorder (OCD) is diagnosed purely based on its symptoms, without regard for underlying neurocognitive causes. This practice entails the likely risk that distinct neural illnesses are diagnosed as a single disorder. The analogy is Parkinsonism, where multiple conditions cause the same symptomatology. This project investigates distinct neurobiological disorders within OCD and determines their neurocognitive phenotypes.</p> <p >In my previous work, I have identified two candidate cognitive phenotypes in OCD, indecisiveness and impaired metacognition. In this fellowship, I will investigate (i) the neural processes underlying these impairments, (ii) the role of neurotransmitter noradrenaline therein, and (iii) determine whether they constitute separable neurocognitive subtypes in OCD. To answer these questions, I will combine simultaneous electroencephalography and functional MRI with pharmacological manipulations, both in healthy volunteers and OCD patients. In addition, I will use large smartphone-based data collection to investigate how indecisiveness and impaired metacognition relate to other cognitive deficits in OCD and to integrate them in a broader landscape of cognitive subtypes in OCD.</p> <p >This project will reveal the neural processes that underlie indecisiveness and metacognitive impairments in OCD. I will determine whether these are separable neural disorders, and whether noradrenaline blockade holds potential as treatment for one of the subtypes.</p>

Amount: £878,701
Funder: The Wellcome Trust
Recipient: University College London