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Deciphering mechanisms of altered neurodevelopment in BAF complex intellectual disability disorders 06 Dec 2017

Intellectual developmental disorder (IDD) is a common yet poorly understood condition. Recent advances in genomic diagnostic technologies have revealed that disruption of genes involved in transcriptional regulation is a leading cause of IDD. Genes encoding the chromatin remodelling BAF swi/snf complex are among the most commonly mutated. Filling the knowledge gap between mutation and disease will contribute to improved patient care and to our overall understanding of human brain development. To that end, I will bridge the clinical and neurodevelopmental biology fields using patient-phenotype informed cellular models to investigate the molecular underpinnings of disease. I will perform deep-phenotyping of a cohort of patients with BAF-complex mutations, and correlate clinical and psychometric features with gene expression and epigenetic signatures in primary tissues. Alongside this clinical study, I will investigate the specific role of ARID1A, an essential BAF complex subunit, in neurodevelopment. Those investigations, performed in induced pluripotent stem cell (iPSC) models of human neurodevelopment, will inform subsequent studies in iPSCs generated from patients. Detailed understanding of clinical outcomes will improve patient management, and integrating the cellular and molecular defects in in vitro models with clinical and molecular phenotypes in patients will help establish predictive preclinical models for translational research.

Amount: £486,911
Funder: The Wellcome Trust
Recipient: King's College London

Combating Gram Negative AMR Pathogens by Understanding the Envelope-Breaching Mechanisms of Predatory Bacteria 28 Nov 2017

We aim to determine the exact molecular mechanisms by which the bacterial predator Bdellovibrio invades Gram negative pathogen prey and whether components of its invasion machinery could be used in isolation as a new approach to the treatment of antimicrobially resistant (AMR) bacterial infections.Gram negative AMR pathogens are a major threat to healthcare. Their "extra" outer membrane is a barrier to effective drug delivery. We wish to learn from nature as Bdellovibrio is able to effortlessly pass through the envelope of pathogen, (but not host), cells and kill them from within. Whole-cell usage of live Bdellovibrio shows great therapeutic promise. However, a deeper understanding of the molecular mechanisms by which Bdellovibrio achieves invasion is essential to inform future therapeutic options. We will use our combined expertise (in microbial-genetics and microscopy, plus protein structure:function analysis of these unusual predators), and preparatory data including:- an RNAseq dataset from an invasion-stalled mutant -providing us with candidate proteins made during invasion; 3DSIM/fluorescence microscopy revealing a central pore, surrounding "collar" and a protein-tagged robust secretory vesicle at the predator-invasion site. Our end goal is to associate specific invasion protein function to these physical features of pore generation/entry, uncovering mechanisms used by nature to breach prey-envelopes.

Amount: £383,881
Funder: The Wellcome Trust
Recipient: University of Birmingham

The role of leukotriene A4 hydrolase in dictating inflammation and remodelling in chronic lung diseases 28 Nov 2017

Whilst inflammation and ensuing repair are critical to the body’s response to infection/injury, aberrant inflammatory and reparative processes and subsequent pathological remodelling are cardinal features of chronic lung diseases (CLDs). I believe the enzyme leukotriene A4 hydrolase (LTA4H) critically regulates inflammation/repair processes through dual activities that generate lipid mediator leukotriene B4 (LTB4) but degrade matrikine Pro-Gly-Pro (PGP). PGP is a neutrophil chemoattractant whilst LTB4 drives the recruitment/activation of numerous immune cells. Additionally, I now demonstrate that PGP regulates epithelial and fibroblast functions critical to repair/remodelling. I hypothesise that intrinsic and extrinsic perturbation of the LTA4H axis drives distinct pathological inflammatory and remodelling phenotypes in CLDs. The key goals of this proposal are: Dissect how the dual functions of LTA4H regulate pathological inflammatory and remodelling features of CLDs, and infer if novel LTA4H modulators show therapeutic potential. Understand how LTA4H is perturbed by genetic influences and environmental insults resulting persistent inflammation and pathological remodelling. Evaluate the LTA4H axis in CLD patients to ascertain why it is aberrant and how it correlates with pathological and clinical endpoints. These studies examine biological pathways that define the balance between health and disease, and will facilitate the endotyping of patients for therapeutic intervention.

Amount: £17,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Cardiovascular risk in Sierra Leone – addressing the burden and barriers 04 Dec 2017

As it recovers from civil war and Ebola, gross domestic product in Sierra Leone is increasing1. This is likely to be accompanied by an increasing burden of cardiovascular disease (CVD) risk factors (RF) with consequent macro- and micro-vascular disease outcomes, as has been seen elsewhere in sub-Saharan Africa.2 Although global studies2-9 estimate prevalence, morbidity, and mortality from CVDRF, nothing is known about the actual burden of CVDRF, provision of care, and barriers to accessing care in the country. This knowledge is essential for designing and implementing cost-effective, equitable interventions to manage CVDRF and mitigate future impacts on individuals, the health system, and the economy, and to enable achievement of Universal Health Coverage. Sierra Leone’s fragile health system makes early intervention for prevention of relatively costly future macro and microvascular outcomes paramout.10 To enable planning of large-scale intervention studies, our key goals for this proposal are to ascertain the burden and correlates of CVDRF in Sierra Leone; estimate 10-year outcomes and costs of mitigating these with early management of RF; and to map potential intervention points by ascertaining a) the barriers to access of care and b) knowledge and attitudes around CVD risk factors amongst the public and providers.

Amount: £96,352
Funder: The Wellcome Trust
Recipient: King's College London

The role of TRIM25's RNA-binding activity in RIG-I/Interferon pathway. 04 Dec 2017

I recently discovered that the TRIM25 E3 ubiquitin ligase, which is a key factor in the innate immune, RIG-I/Interferon type 1 response to RNA viruses, is an RNA-binding protein that recognises specific host RNAs and regulates their stability. This important finding redefines our understanding of the regulation of host RNA metabolism and opens new questions about the fundamental mechanisms of cell biology and innate immunity. My overall goal is to discover new phenomena occurring at the interface between RNA biology and human disease. Here, I will focus on what role does newly identified RNA-binding activity of TRIM25 have in innate immune response to 5'-ppp-RNAs and Influenza A infection. Towards this aim, I will address the following: How does the RNA-binding activity of TRIM25 affect its ability to stimulate the RIG-I/Interferon signalling pathway? The outcome of this research will redefine our understanding of the control of RIG-I/Interferon signalling pathway and has huge potential to open up novel research avenues in the field of innate immunity and RNA biology.

Amount: £87,429
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Opening Up the Body: The Post Mortem Case Books of St George's Hospital 16 Nov 2017

The Opening Up the Body project aims to conserve the Post Mortem Examinations and Case Books of St George’s Hospital, 1841-1946, and to catalogue and digitise those dating from 1841-1917 (see ethics section for details). This will enable access for academic research and public engagement activities. These historical records, which chart the golden age of the post mortem, from its heyday in the 19th century to its subsequent decline in the second half of the 20th century, will be made accessible in partnership with the London Metropolitan Archives (LMA) and the Leather Conservation Centre (LCC). Conservation of the leather will be undertaken by the LCC, and digitisation and minor repairs of the text block will be carried out by LMA in their dedicated studios. Two project archivists, based at St George's, University of London, will catalogue the collection under the supervision of the university archivist. The catalogue data and digitised images will be searchable through AtoM (Access to Memory) software and will be available on the St George’s, University of London website. The collection will be promoted through a number of relevant archive and medical humanities networks to increase accessibility to academic researchers and other interested parties.

Amount: £159,862
Funder: The Wellcome Trust
Recipient: St George's University of London

Crafting Qualitative Health Research for the Future 04 Dec 2017

Healthcare environments across the globe are encountering new challenges as they respond to changing populations, global austerity, rapid technological advances, personalised medicine, and demands for more patient involvement. We believe that qualitative health research (QHR) can contribute to our understanding and responses to these challenges, and we have developed a proposal which aims to expand and improve the work of this field. This proposed work will be conducted through our UCL Qualitative Health Research Network (QHRN) and will include the following activities: 1) a networking and brainstorming event to create a forum for the critical analysis and improvement of QHR; 2) the fourth QHRN symposium, a two-day event with 200 delegates, 20 oral presentations and 40 posters; and 3) our quarterly seminar series, which showcases presentations from leading scholars in QHR. The main outputs generated through these events and activities will include: A position paper detailing recommendations for the improvement of QHR, publication of our proceedings from the symposium in a peer-reviewed journal, workshops and other training opportunities at the QHRN Symposium, the continuation of communication channels for members of the network (website, email listserv, and Twitter account), and dissemination of findings of QHR to patient organisations, practitioners and policymakers.

Amount: £29,198
Funder: The Wellcome Trust
Recipient: University College London

Bucket Loads Of Health 31 Oct 2017

The drought that is currently affecting Cape Town has driven the implementation of maximum level water restrictions. To meet these requirements, city residents are experimenting with various water saving methods, including harvesting rainwater and recycling grey water for household use. Bucket Loads Of Health responds to the multiple health risks that are associated with these approaches to reusing water. The project will engage residents from three communities that vary significantly in water availability. Through a series of participatory audio-visual workshops, the community participants will explore their individual and collective experiences of water shortage and water saving. The workshop outputs - including body maps, personal stories, musical narratives and short films - will create platforms for co-learning between the community participants, water scientists, government representatives and other community members. These engagements will enable the exchange of knowledge about how water saving efforts can compromise health, and generate new thinking about practical measures to make these efforts safer. This work will emphasize the importance of public engagement in making scientific research more accessible and relevant to communities and policy makers. It will also enable policy makers to draft guidelines underlining the health-related aspects of water saving and reuse in different contexts.

Amount: £93,000
Funder: The Wellcome Trust
Recipient: Sustainable Livelihoods Foundation

The Legal and Social Life of Care Standards Regulation in England, Scotland and Wales. 30 Nov 2017

Poor quality employment for careworkers damages the quality of adult social care provision. By investigating the socio-legal capacity for care standards regulation to influence the quality of careworkers’ jobs, this project supports practical improvement in service delivery and will expand regulatory know-how. The research is an interdisciplinary proof-of-concept study investigating how the legal regulation of care standards shapes the job content and terms and conditions of careworkers. Making comparison across three UK nations, its context is the ‘struggle to get people to work in the care sector and retain them' (Age U.K 2017:55). It advances a novel research agenda in a regulatory landscape characterised by the clear and urgent social connectedness of care quality to job quality (Francis, 2013) and the legal separation of employment standards from care standards. Taking a comparative approach, the project will work with inspectors, commissioners and employers to explore how the ‘social life’ of care standards regulation shapes careworkers’ employment and impacts on care quality in so doing. It begins by mapping legal regulations / regulatory systems and then examines how social care standards are dynamically interpreted/translated at different levels of regulatory systems (ie in the social practices of inspection, service commissioning and hiring careworkers).

Amount: £71,204
Funder: The Wellcome Trust
Recipient: Cardiff University

A Case for the Ordinary: The Patient Experience of Mental Health Care in Staffordshire, 1818-1960 16 Nov 2017

This innovative cataloguing project will make accessible case notes of 38,000 patients treated in Staffordshire's three County Asylums, from 1818 to 1960. Collaboration with academic partners at the concept stage has ensured that research imperatives are addressed, with a particular emphasis on access to information in 20th-century patient records. The resources produced will be an open catalogue of early patient case files and a database of extracted information from case files less than 100 years old, the latter available through a simple access process agreed with our NHS Trusts. The method of cataloguing will permit a rolling programme of uploading newly open data to the catalogue and the ongoing involvement of our project advisory board will ensure that the resources have a wide academic reach. The breadth, completeness and representativeness of the Staffordshire collection and the resources produced by this project will offer a unique opportunity to interrogate data from patient case records for specific themes over an unprecedentedly long period. Staffordshire saw pioneering approaches in mental health care but conversely these records also provide an exceptional resource for studying the experience of ordinary English provincial patients at multiple sites over the broad sweep of public asylum history.

Amount: £167,519
Funder: The Wellcome Trust
Recipient: Staffordshire County Council

Developing public and professional engagement to promote global policy and a new research vision to improve the health of labour migrants 04 Dec 2017

Population mobility within and across borders is becoming increasingly complex, yet there has been little synthesis of evidence or expert consultation on the wide-ranging health implications of migration. Indeed, the largest migrant group – labour migrants - have been excluded from the research agenda to date, with little known about the health consequences for the families they leave behind. The UCL-Lancet Commission on Migration and Health aims to consolidate evidence and generate new insights into the interactions between migration and health. The proposed project aims to support the work of the Commission by: a) identifying and synthesising data through two systematic reviews and meta-analyses on labour migrants and left-behind children; b) gaining expert insights, including convening a stakeholder meeting to assess evidence and generate innovative solutions and evidence-based recommendations; c) develop a public engagement strategy to foster shared expertise in this area; and d) define first steps towards establishing a new Global Observatory on Migration and Health that will seek to promote knowledge generation, translation, and monitoring of global and regional standards to improve health outcomes related to migration.

Amount: £40,272
Funder: The Wellcome Trust
Recipient: Imperial College London

UCL Unit for Stigma Research: Advancing theory and practice in the stigma field 04 Dec 2017

Our new UCL Unit for Stigma Research (UCLUS) will be a hub for innovative high quality research and theory production in the field of stigma research. UCLUS brings together research across diverse fields, including intellectual disability, mental health and dementia, and explores cross-cutting themes and opportunities for research. We are seeking funding to support UCLUS activities and explore areas for new research on stigma resistance and disclosure decision making, two novel areas in which we are piloting work. A better understanding of what makes some members of highly stigmatised groups more vulnerable/resistant to stigma, and how they manage disclosure offers the potential for innovative contributions to broader theorising on responses to adversity. It can also inform the development of interventions that enhance wellbeing via capacity to resist stigma among members of highly stigmatised groups. Funding will allow us to (a) explore this area further, (b) develop a research agenda, (c) build capacity for high quality research, and (d) extend existing and form new partnerships to take this work forward through the public launch of UCLUS, a seminar series, development of the research unit's social media presence, a UCLUS led session at the 2018 IASSID European Congress, and international collaborative visits.

Amount: £29,633
Funder: The Wellcome Trust
Recipient: University College London

Malawi Liverpool Wellcome Trust Programme - Core Award 01 Jun 2017

We will achieve internationally excellent translational science to benefit human health with a focus on sub-Saharan Africa. MLW is built around excellent laboratories, strategically located in the largest hospital in Malawi, closely linked with the community and an integral part of the medical school. These relationships provide a valuable opportunity replicated in few centres in Africa to study major health issues spanning both community and hospital. We will manage two major Programmes: (1) Preventing death from severe infection, and (2) Transmission reduction in infectious diseases and continue to publish over 100 papers/year. Over the next 5 years, we will target clinical syndromes of sepsis, meningitis, diarrhoea and pneumonia with vaccine, behavioural and clinical management strategies. We will focus on transmission of HIV, TB and malaria with improved access to care, diagnosis and treatment. In addition, a Strategic Initiative will target selected high burden chronic diseases (lung impairment, stroke, blindness), particularly related to HIV. In partnership with the College of Medicine we will deliver Training that will attract, train and retain local and international senior scientists. Through our partnership with the Ministry of Health, our Policy Aims will ensure that our research is both relevant and applied to improve human health.

Amount: £25,084,066
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Virtual Fly Brain 06 Jul 2017

Neuroscience is accelerating: the capability to generate circuit level hypotheses is now matched with the ability to visualise, manipulate and record from individual neurons, in vivo. Drosophila, with its complex adaptive behaviors, powerful genetic toolkit and small nervous system, for which we will soon have complete connectomes, is uniquely placed to contribute to this work. Virtual Fly Brain (VFB) is a unique resource for Drosophila neuroscience, integrating disparate, large-scale datasets and linking them to curated literature and other resources. VFB works with international data providers and bioinformatics resources to ensure efforts are complementary, non-redundant, and make best use of resources. VFB users browse and query curated information from many sources to understand structure, function and relationships in the brain. Critically, VFB provides the data to generate circuit hypotheses and identify research tools to test them. This proposal continues this vital service and extends it to incorporate rich new data types. We will incorporate synaptic resolution connectomic data, develop bridging registrations to make it bidirectionally queryable from light level data. We will add phenotypic and transcriptomic datasets and enhance tools that enable researchers to find reagents. We will enable users to upload, view and query their own 3D datasets.

Amount: £996,004
Funder: The Wellcome Trust
Recipient: University of Cambridge

Data sharing platforms to improve treatment outcomes in neglected tropical diseases 06 Jul 2017

We will develop data-sharing platforms to assimilate and collaboratively interrogate global data on i) schistosomiasis ii) soil transmitted helminths, iii) visceral leishmaniasis, iv) melioidosis and v) scrub typhus. This proposal will support the development of the technical platform and curation of data from tens of thousands of patients enrolled to treatment trials and programmatic data of these diseases for use in collaborative meta-analysis to answer key public health questions. The platform’s technical infrastructure will include secure data upload, auditable mapping of multi-disciplinary datasets to a standardised data structure, searchable data inventory and systems to request and receive data. The governance framework will ensure terms of data access that follow principles of equitable and ethical data sharing under the guidance of Science Advisory Committees nominated by the relevant disease communities. Support for the coordination and production of scientific output from the platform will be provided to ensure impact. Platform construction will leverage the expertise and investment in our existing malaria data platform, the WorldWide Antimalarial Resistance Network (WWARN). Prior funding has supported the development of successful pilot platforms for visceral leishmaniasis and schistosomiasis/soil-transmitted helminths, and we will assess the feasibility and impact of establishing platforms for melioidosis and scrub typhus.

Amount: £1,406,744
Funder: The Wellcome Trust
Recipient: University of Oxford

Re-imagining The Workhouse 16 Mar 2017

As we approach the 70th Anniversary of the Welfare State, this project will deliver a completely new visitor experience at The Workhouse and it will allow our audiences to explore welfare development and the perennial connection between wealth and health. For nearly 200 years the site of The Workhouse at Southwell has been used for the provision of welfare to those most vulnerable in society. The Workhouse became a prototype for a national attempt to revolutionise the treatment of those in poverty, and which legacy continues to evoke powerful contemporary debate. We are re-imagining our site to tell this changing story of welfare and health: from Poor Law to Welfare State; from Paupers to Patients. The Workhouse was acquired as the National Trust’s first learning property with a vision to move from ‘memory to action’. While we will continue to support formal learners, we will use our 1871 infirmary building, currently empty and inaccessible, to also focus our learning, creative and community programmes around those who can benefit most from the site, to ‘live its history’ and support those most in need to flourish through education and opportunity. This project will improve physical and intellectual access to our site, with powerful, evolving interpretation, which makes accessible and fully utilises 20 years of research. We will offer a multi-layered experience, which goes beyond telling the story, but to affecting change: by inviting people to share experiences, engage in contemporary debates and to raise awareness of health and welfare issues today.

Amount: £365,924
Funder: The Wellcome Trust
Recipient: The National Trust

Contact capital project 16 Mar 2017

We are proposing a major capital redevelopment of our building, designed to transform the public and user experience of Contact - improving flow, circulation and readability across a series of outstanding public and artistic spaces. The project will extend the footprint of the current venue and reconfigure the interior to create new, flexible creative and learning spaces and improve our performance and working spaces – so increasing opportunities for young people. It will create a more open, accessible and welcoming public environment, both within and in the approach to the building. Technical infrastructure will be upgraded across the entire building and soundproofing improved. Works will include a range of measures designed to strengthen Contact’s environmental sustainability and to improve accessibility. Within this broader context we propose to create, with support from the Wellcome Trust, a dedicated new space on Contact’s ground floor, adjacent to the public foyer and café area and accessed directly from outside, to act as the ‘engine room’ for Contact’s creative activity around health sciences and related social issues. Through this space we plan to maximise cross-sectoral working and engagement between diverse young people and science and research communities. The space will provide a dynamic, accessible and stimulating public window into an integrated programme of creative engagement with health science research, led by a dedicated Health and Science Producer and embedded right across Contact’s creative development practice. The space will also provide an performance capabilities for public work-in-progress sharings, as well as debates, discussions and panel events.

Amount: £603,500
Funder: The Wellcome Trust
Recipient: Contact

Role of Inhibitor of Kappa B Kinase Epsilon in Sex-dependent Differences in Metaflammation 19 Apr 2017

With the failure in curbing the global obesity epidemic, there is an urgent need to develop therapies to treat obesity-associated metabolic diseases. This requires a better understanding of the molecular mechanisms that not only promote, but also prevent metabolic disease development. Although, chronic low-grade inflammation ("metaflammation") is an important causative factor in metabolic diseases, the anti-inflammatory effects of estrogens may provide important insights into disease prevention. Indeed, pre-menopausal women are protected from obesity-linked metabolic diseases. Previously, I have identified immunometabolic proteins, e.g. IKBKE, that limit metabolic stress-induced inflammation and these are influenced by sex. However, it remains unclear whether, and how, estrogens alter innate immune sensitivity to metabolic stress. This project will address this and test the hypothesis that both estrogen- and IKBKE-dependent pathways function in a common signalling network to regulate energy balance and metaflammation. I will investigate, invitro and invivo, the synergies that exist between estrogen- and IKBKE-depended actions in metaflammation. Ultimately, the knowledge gained may support the notion that estrogens and IKBKE are key in raising the threshold for metabolic stress-induced inflammation. This may identify novel therapeutic targets to treat obesity-linked metabolic diseases and shed light on the immunometabolic changes that accompany menopause in all ageing women.

Amount: £589,119
Funder: The Wellcome Trust
Recipient: University of Southampton

Unravelling the molecular complexity behind ocular maldevelopment 30 Sep 2017

Aim: Investigating the relationship between genotype, gene expression and phenotype of microphthalmia, anophthalmia and ocular coloboma (MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide. Research questions: What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk? What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia? Key goals and methodology: Whole genome sequencing of 30 parent-offspring trios with isolated MAC and longitudinal phenotyping. Establish an international reference network to stratify a well-defined cohort to improve care pathways and future research. Temporal comparative analysis of DNA methylome (bisulfite conversion and Illumina Infinium EPIC BeadChips) and transcriptome (65 million reads per sample using Illumina HiSeq-2500) in the developing human eye between 4-9 weeks gestation. Model 3D human microphthalmic optic cups using iPSC technology with isogenic controls using CRISPR/Cas9 gene-editing. DNA methylome and transcriptome analysis to assess disruption of molecular pathways. Outcomes: Establish a molecular framework for ocular maldevelopment. Identify drug targets and develop therapeutics. Improve genetic diagnosis, counselling and management. Elucidate shared molecular mechanisms between embryonic tissue fusion defects and late-onset visual sensory disorders.

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

Integrating Ethics and Equity into Priority Setting for Universal Health Coverage: A Proof-of-Concept Study in South Africa 25 Jul 2017

Priority-setting for health is morally complex with unavoidable trade-offs. Policymakers face ethical dilemmas in healthcare coverage decisions. With many countries pursuing Universal Health Coverage, health technology assessment (HTA) has become a popular approach to health decision-making. HTA evaluates the value-for-money of different health interventions while providing a mechanism to facilitate transparent and inclusive decision-making. Although ethics is stated as a core component of HTA, and theoretical HTA ethics frameworks exist, the uptake of ethics analysis in HTA is limited. Few studies have explored practical implementation and impacts of systematic ethics analysis in HTA. This "proof-of concept" study in South Africa will generate evidence on how a context-specified ethics framework for health priority-setting can be developed and the influence its application may have on HTA recommendations – with the potential to impact near-term decisions for the National Health Insurance (NHI) policy rollout and longer-term approaches to HTA in South Africa and beyond. With key stakeholders, we will co-produce an ethics framework to guide NHI decision-making, then evaluate how applying the framework influences HTA recommendations. Findings will be widely disseminated, presenting impacts on coverage recommendations, resources required to develop and apply the framework, and implementation considerations for systematic ethics analysis in HTA.

Amount: £128,944
Funder: The Wellcome Trust
Recipient: Imperial College London