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Funders:
The Wellcome Trust

Results

GeneFriends: A gene and transcript co-expression resource 06 Jul 2017

GeneFriends is an online (http://genefriends.org/) gene and transcript co-expression resource which allows researchers to assign putative functions to poorly annotated genes/transcripts as well as identify and rank new candidate genes related to any disease or process using a guilt-by-association approach. In this project, we aim to build upon the work done thus far, by maintaining, expanding and enhancing existing resources and by developing new functionalities. Specifically, the goals of this proposal are: 1. Update and enhance the current GeneFriends databases and tools by updating the underlying datasets and developing network visualization features. 2. Allow users to create co-expression networks from their own data uploaded to GeneFriends by developing a suitable pipeline and by implementing a user-friendly web page to return results to users. 3. Allow users to select/add extra gene expression datasets to create customized co-expression networks; this will involve creating a compilation of pre-processed publicly available gene expression data and metadata plus adapting our existing pipelines for data processing and co-expression network construction. Given the growing importance of next-generation sequencing, GeneFriends will greatly benefit the research community. Overall, GeneFriends is a powerful approach for the analysis and interpretation of genetics and genomics data from different types of studies.

Amount: £213,244
Funder: The Wellcome Trust
Recipient: University of Liverpool

The Nomenclature of Human and Vertebrate Genes 06 Jul 2017

As human genomics is already a crucial aspect of biomedicine, with increasing importance in clinical practice and everyday life, communicating in a common language about genes becomes ever more vital. The HUGO Gene  Nomenclature Committee (HGNC) is the sole worldwide authority assigning standardised nomenclature to human genes, and maintains a searchable database of over 40,000 named human genes at www.genenames.org. This funding will enable the continuance of the crucial work of the HGNC, in particular naming newly identified protein-coding and RNA genes and pseudogenes. A further key activity will be the reassignment of genes with uninformative identifiers to function-based names as this information is elucidated. The HGNC will also continue to play a pivotal role in consensus annotation of the remaining unresolved gene structures in the human genome. HGNC recently established the Vertebrate Gene Nomenclature Committee (VGNC, vertebrate.genenames.org), a sister project for naming genes in other vertebrates utilising data from phylogenetic resources and in collaboration with specialist advisors for complex gene families

Amount: £1,215,543
Funder: The Wellcome Trust
Recipient: Embl At Hinxton

Medicine Galleries Project - Development Grant 30 Sep 2017

Fellowships which will support the aims of the Science Museum’s medicine collection research strategy. The aims are: 1. To benefit, directly, or indirectly, to the development of the Medicine Galleries project.2. To deepen our understanding of the Science Museum’s medical collection.3. To enable greater cooperation between curators and academics.4. To build the Science Museum’s reputation as a research hub for the medical humanities and Social Sciences.

Amount: £300,000
Funder: The Wellcome Trust
Recipient: Science Museum

Tackling Histoplasmosis; a neglected disease impacting on equine health and human livelihoods. 25 May 2017

Histoplasmosis is a neglected yet prevalent disease among working equids in sub-Saharan Africa where horses provide a critical source of income and draught power for transport and agriculture to millions of people. There is a lack of evidence for the mechanisms of transmission and persistence of histoplasmosis offering little rationale upon which to base disease control. This novel multidisciplinary study will combine epidemiological, ecological and community engagement approaches to investigate the dynamics of this endemic disease, and will be achieved through an international collaboration across the academic, veterinary and NGO sectors. Phase 1 comprises a prospective multi-centre cohort study, a nested case-control study, and a clinical case-series. Clinical and environmental samples will be collected along with epidemiological data to determine the contribution of environment and host factors to both susceptibility and response to the disease. Clinical samples will be analysed using serological and molecular biological techniques to determine the presence and state of infection and to characterise Histoplasma diversity. Single-cell genome sequencing will be used to define predominant and/or virulent strains. Phase 2 will involve consultation with the community and regional stakeholders to share research findings and develop and disseminate disease prevention advice facilitated by the NGO partners.

Amount: £937,371
Funder: The Wellcome Trust
Recipient: University of Liverpool

Schwann cell-axonal communication during axonal degeneration and regrowth 25 May 2017

Myelinating and non-myelinating Schwann cells are reprogrammed after nerve injury into repair Schwann cells, specialized for maintaining survival of injured neurons and supporting axonal regeneration. This process is regulated by Schwann cell-intrinsic signals, such as the transcription factor c-Jun, however few other candidates have been identified. It is, currently, unknown how Schwann cell reprogramming is initiated, but unidentified extrinsic signals from injured axons are likely candidates. I aim to delineate the spatial and temporal regulation of Schwann cell-intrinsic downstream signals in real-time and define their role in repair Schwann cell function and axonal regeneration. Secondly, I aim to test the hypothesis that axon-derived signals initiate Schwann cell reprogramming during nerve injury. I will use cell culture, in vivo mouse models and a live and dynamic zebrafish larval model of nerve injury. This study will be the first to investigate how axon-intrinsic mechanisms of nervous system injury interplay with glial cell molecular responses to nerve damage, in real-time. Using cutting edge techniques in two species, this project will significantly advance our understanding of Schwann cell-axonal biology and tissue repair. Excitingly, this research may identify new potential therapeutic targets to improve poorly regenerating human nerves and treat patients with neuropathies.

Amount: £426,876
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding cross-reactive immunity to Japanese encephalitis virus 06 Dec 2016

The flavivirus Japanese encephalitis (JE) virus (JEV) causes devastating disease in thousands of Southeast Asian children every year. The sequence of flavivirus infection and cross-reactivity are important determinants of immunopathogenesis, but these phenomena are understudied outside dengue. A deeper understanding of immunological cross-reactivity will underpin development of next-generation flavivirus vaccines and novel therapeutic approaches. The sequence of flavivirus infection is hard to confirm in endemic areas, and initial exposure usually occurs in early childhood—this makes field studies difficult and alternative approaches are urgently required.The key goals of this Fellowship are:1. Develop a human experimental model of JEV infection using live JE vaccine in flavivirus-naïve adult volunteers and previously yellow fever vaccinated subjects.2. Identify conserved epitopes between flaviviruses that may serve as targets for novel vaccines and therapeutics.3. Train in advanced B cell immunology techniques, including the development of human JEV monoclonal antibodies and flavivirus B cell epitope mapping.This programme of work will provide new insights into JE pathogenesis, further elucidate fundamental principles of flavivirus immunology and provide new tools to develop better therapeutics for this important and understudied disease. The training opportunities will help me develop as a leader in viral immunology and experimental medicine.

Amount: £653,257
Funder: The Wellcome Trust
Recipient: University of Liverpool

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.

Amount: £516,560
Funder: The Wellcome Trust
Recipient: University of Cambridge

Which maternal infections are associated with stillbirths and early neonatal deaths, in East Africa? 06 Dec 2016

Reducing neonatal deaths and stillbirths is an international public health priority, yet the contribution of vertically-acquired infection, potentially amenable to intervention, is unclear, with essentially no data from the highest mortality settings. I propose to provide a robust description of the association of maternal infection with stillbirths and early neonatal deaths by studying mothers delivering in a moderate mortality setting in Kilifi, Kenya, and in Harar, Ethiopia, where the under-5 mortality ratio is three-fold higher than in Kilifi, Kenya. I will begin by investigating mothers in Kilifi County Hospital, Kenya, from a well-characterised existing maternal cohort (2011-16) in a case-control design (n=700). Laboratory investigation using nucleic acid detection on stored blood samples will be done at the internationally accredited KEMRI-Wellcome Trust Research Programme laboratories. Then, in a prospective study in Hiwot Fana Hospital, Harar, Ethiopia, I will recruit and investigate mothers (2017-19) in the same case-control design (n=700). Laboratory investigation on site will include both conventional and nucleic acid detection methods. This study utilises a new site for the Child Health and Mortality Prevention Surveillance (CHAMPS) network. As this network extends, it will create the opportunity to use this work to design community studies and large scale intervention trials.

Unravelling the molecular complexity behind ocular maldevelopment 06 Dec 2016

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: £1,133,875
Funder: The Wellcome Trust
Recipient: University College London

Using visual dysfunction to understand dementia in Parkinson’s disease 06 Dec 2016

Dementia affects half of patients with Parkinson’s disease (PD) but there are no robust measures to predict who is at highest risk. Visual hallucinations are highly distressing to patients and carers but are poorly understood. This Fellowship will use visuo-perceptual dysfunction to predict dementia and understand hallucinations in PD. I have developed a novel test using skewed images to detect visuo-perceptual deficits in Parkinson’s patients. I have also developed a web-based platform to enable this and other visual tests to be accessed by large numbers of patients with PD. In this proposal I will use visual perceptual tests combined with neuroimaging over time to determine the sequence of visuo-perceptual deficits in PD. I will relate these to changes in hallucinations. I will use my web-based platform to identify clinical and genetic associations with visual deficits and determine their role in predicting dementia in PD. Goals 1. Characterise changes in visuo-perception as PD progresses and correlate deficits with brain atrophy. 2. Relate MRI structural connectivity changes with disease progression. 3. Examine clinical and genetic associations of visual dysfunction in PD. 4. Test whether transcranial stimulation can improve visuo-perceptual function in PD. 5. Determine how visual hallucinations become distressing as PD advances.

Amount: £1,223,282
Funder: The Wellcome Trust
Recipient: University College London

The role of BMP signalling in diseases of the motor unit 06 Dec 2016

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neuromuscular disease characterized by lower motor neuron degeneration as result of misfolding and accumulation of mutant Androgen Receptor (AR). In recent years this scenario of selective neuronal vulnerability has been challenged by the discovery that in SBMA, as in other diseases of the motor unit, skeletal muscle, rather than being a mere bystander of motor neuron degeneration, is primarily affected and therapies exclusively targeting muscle ameliorate the pathology in motor neuron while preventing the development of a neuromuscular phenotype in animal models. My goal is to elucidate the molecular mechanisms underlying the intrinsic contribution of skeletal muscle in SBMA pathogenesis. I will investigate the role of the Bone Morphogenetic Protein (BMP) signalling pathway in SBMA pathophysiology, testing the central hypothesis that failure to activate the protective BMP pathway in SBMA muscle in response to denervation causes primary muscle atrophy and affects motor neuron ability to cope with the stress posed by mutant AR. The rationale is to provide a molecular basis for the cell-autonomous and non-cell autonomous roles of muscle in the mechanisms of toxicity in SBMA and other diseases of the motor unit and to identify novel therapeutic targets.

Amount: £1,048,938
Funder: The Wellcome Trust
Recipient: University of Oxford

Facilitating ethical preparedness in genomic medicine 25 Jul 2017

This collaborative research programme will combine empirical bioethical research, conceptual, and theoretical analysis to examine the issue of ethical preparedness in the context of genomic medicine, and to inform and develop relevant policies for practice. We will conduct our research as genomic approaches to diagnosis and treatment, such as the 100,000 genome project, become embedded within health care. We will focus on the extent to which professionals are prepared for navigating the ethical issues within the new working environment of clinical genomics; one where research and clinical practice are more co-dependent than in the past, and where responsibilities of care, both to one person over time as well as to their current and future relatives are changing. The programme will utilise a range of research methods across a variety of settings to map the experience of practitioners, patients and participants in genomic medicine, the ethical issues they confront, and the impact on practice when these are challenging of their established practice, be that at the stage of recruitment/ introduction, diagnosis (or lack of), treatment, surveillance, longer term contact or need for contact of other .

Amount: £537,165
Funder: The Wellcome Trust
Recipient: University of Southampton

Facilitating ethical preparedness in genomic medicine 25 Jul 2017

This collaborative research programme will combine empirical bioethical research, conceptual, and theoretical analysis to examine the issue of ethical preparedness in the context of genomic medicine, and to inform and develop relevant policies for practice. We will conduct our research as genomic approaches to diagnosis and treatment, such as the 100,000 genome project, become embedded within health care. We will focus on the extent to which professionals are prepared for navigating the ethical issues within the new working environment of clinical genomics; one where research and clinical practice are more co-dependent than in the past, and where responsibilities of care, both to one person over time as well as to their current and future relatives are changing. The programme will utilise a range of research methods across a variety of settings to map the experience of practitioners, patients and participants in genomic medicine, the ethical issues they confront, and the impact on practice when these are challenging of their established practice, be that at the stage of recruitment/ introduction, diagnosis (or lack of), treatment, surveillance, longer term contact or need for contact of other .

Amount: £583,569
Funder: The Wellcome Trust
Recipient: Brighton and Sussex Medical School

21st Century Families: Parent-child relationships and children's psychological wellbeing 25 Jul 2017

New pathways to parenthood have recently emerged that did not exist, nor had even been imagined, at the turn of the 21st century. Individuals who were previously unknown to each other have begun to meet over the internet with the purpose of having children together; transgender men and women have begun to have children through medically assisted reproduction; single heterosexual men have begun to use surrogacy to become single fathers by choice; and women have begun to use identifiable egg donors to have children. These emerging family structures raise new ethical, social and psychological concerns, particularly regarding the potentially negative consequences for children. The proposed research will provide empirical evidence from a multidisciplinary perspective on the social and psychological consequences for children of growing up in family arrangements involving non-cohabiting co-parents, transgender parents, elective single fathers and identifiable egg donors. In this emotive area of family life on which people often hold strong opinions, our aim is to challenge prejudice and assumption with evidence on the actual consequences – good, bad or neutral – for children. The ultimate goal of the proposed research is to increase understanding of diversity in family life and improve the lives of 21st century children.

Amount: £1,552,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

‘People like you’: contemporary figures of personalisation 01 Feb 2017

We aim to contribute to critical medical humanities by investigating an emergent culture of personalisation in the UK, associated concepts of the person and health. We expect to stimulate debate on personalised medicine by showing how it can be understood more fully in relation to other personalising practices and how features shared across this broad field are consequential for our wellbeing. Our innovative figural approach will be applied to case studies of both top-down and open-ended practices of personalisation in medicine, data science and digital culture. In collaboration with creative consultants, we will conduct practice-led research to produce additional insight into the role of participation in, and the sense made of, personalisation. Our aim is to put the ‘person’ back into personalisation, and relate such persons to the data collected from them and on their behalf. This approach will allow us to investigate individuals’ sense of self, agency and identification with others. It will allow us to consider the implications of new techniques for stratifying ‘persons’ precisely in shaping health outcomes and healthcare priorities. In sum, we will assess whether personalising practices, considered together, are influencing taken-for-granted concepts of the person with consequences for individual and collective health.

Amount: £368,906
Funder: The Wellcome Trust
Recipient: University of Warwick

The Animal Research Nexus: Changing Constitutions of Science, Health and Welfare 01 Feb 2017

This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.

Amount: £351,802
Funder: The Wellcome Trust
Recipient: University of Nottingham

Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All 11 Jul 2017

Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities. However, progress in achieving such behaviour change is slow. Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities. Conversely, Choice Architecture interventions ("Nudges") have potentially larger, more equitable effects, involving re-designing environments e.g. reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited. We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising Choice Architecture interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms. We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.

Amount: £3,123,724
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanics and execution of homologous recombination - biophysics to the organism 11 Jul 2017

Homologous recombination (HR) is an essential mechanism for the repair of DNA double-strand breaks and damaged replication forks and is associated with genetic disorders, cancer and aging. HR repairs DNA damage by copying the correct genetic information from an intact chromosomal template, which is critically dependent on the recombinase RAD51. To ensure its timely and accurate completion, HR is positively and negatively regulated by RAD51 co-factors and anti-recombinases. How these HR regulators function at the molecular level remains poorly understood and represents a significant challenge to the field due to the lack of mechanistic resolution afforded by conventional bulk biochemical approaches. We recently pioneered several cutting-edge biophysical approaches to interrogate the HR reaction in unprecedented detail. Importantly, we demonstrated the power of integrating data from these complementary methodologies to uncover the mechanism of action of the Rad51 paralogs in modulating RAD51 to promote HR. The aim of our proposal is to extend this paradigm to study multiple different HR regulators to gain insights into how they work individually and how they act cooperatively during HR. Deciphering how HR regulators work will provide an improved understanding of the molecular mechanisms relevant to carcinogenesis and may present unique opportunities for therapeutic intervention.

Amount: £573,417
Funder: The Wellcome Trust
Recipient: Columbia University

Mechanics and execution of homologous recombination - biophysics to the organism 11 Jul 2017

Homologous recombination (HR) is an essential mechanism for the repair of DNA double-strand breaks and damaged replication forks and is associated with genetic disorders, cancer and aging. HR repairs DNA damage by copying the correct genetic information from an intact chromosomal template, which is critically dependent on the recombinase RAD51. To ensure its timely and accurate completion, HR is positively and negatively regulated by RAD51 co-factors and anti-recombinases. How these HR regulators function at the molecular level remains poorly understood and represents a significant challenge to the field due to the lack of mechanistic resolution afforded by conventional bulk biochemical approaches. We recently pioneered several cutting-edge biophysical approaches to interrogate the HR reaction in unprecedented detail. Importantly, we demonstrated the power of integrating data from these complementary methodologies to uncover the mechanism of action of the Rad51 paralogs in modulating RAD51 to promote HR. The aim of our proposal is to extend this paradigm to study multiple different HR regulators to gain insights into how they work individually and how they act cooperatively during HR. Deciphering how HR regulators work will provide an improved understanding of the molecular mechanisms relevant to carcinogenesis and may present unique opportunities for therapeutic intervention.

Amount: £852,114
Funder: The Wellcome Trust
Recipient: Imperial College London

State of the art cryo electron microscope for molecular and cellular biology 07 Dec 2016

Dramatic advances in the power of cryo electron microscopy (EM) to resolve macromolecular and cellular machinery have greatly expanded the field and our need for access to state-of-the-art microscopes. With its internationally renowned research programme on macromolecular machines, the ISMB EM lab is ideally placed to benefit from recent instrumental developments. Although the eBIC facility at Diamond helps by providing intermittent access to state of the art 300 kV systems, this cannot sustain our large research programmes and expanding user base without substantial in-house facilities. Our ever-increasing number of structural and cell biology users are now waiting 3-5 weeks for access to high-end microscopes. Our recent equipment award contributes to an intermediate, 200 kV system, suitable for single-particle work but sub-optimal for tomography and cell biology, limiting its wider impact. In contrast, a 300 kV machine, with cutting-edge performance for single particles, unique assemblies, and cellular sections, would have a transformative impact, enabling new research from a wider community including outstanding local cell biologists. Therefore, we request a Cryo-EM Equipment Grant to upgrade from the 200 kV system to a high-end 300 kV system to be accommodated by an expansion and reorganisation of our EM laboratory.

Amount: £2,340,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London