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Results

Life-course determinants and prevention of violence 10 Apr 2018

I will use a life-course epidemiological approach to investigate determinants and prevention of violence, based on four population-based birth cohort studies (N > 4,000 in each) started in 1982, 1993, 2004, and 2015 in Pelotas city, southern-Brazil. My goals are to: 1) investigate early life-mechanisms hypothesised to cause persistent child aggression leading to violence; 2) investigate reasons for the rapid increases in violence during the course of the studies; and 3) evaluate two early interventions to prevent child behaviour problems leading to violence, in a randomised-control trial nested in the youngest cohort study (2015). With respect to early-life determinants, new psychological assessments of child socio-cognitive functioning (including self-control, verbal skills, and empathy) and parenting factors (sensitivity, harsh and inconsistent parenting) will be introduced in the youngest cohort, and a biological indicator of chronic stress (cortisol from hair samples) will be measured in the 2015 and 2004 cohorts. A four-arm randomised trial will be used to evaluate the effects of two parenting interventions: 1) parent-training in book-sharing to promote parental sensitivity and child cognitive development – key protective factors against aggression and violence; 2) parent-training that targets a reduction in harsh discipline and maltreatment – also key risk factors for problem behaviour.

Amount: £2,184,175
Funder: The Wellcome Trust
Recipient: ABRASCO

Causes and Consequences of Pathological Adipose Remodelling 10 Apr 2018

This proposal addresses two factors important in obesity-related disease, namely determinants of healthy adipose remodelling in chronic positive energy balance, and mechanisms linking insulin resistance to disease. Two rare, informative human disorders will first be dissected, one featuring subcutaneous lipodystrophy due to heterozygous loss of DNA polymerase delta activity and the second a mixture of lower body fat loss and dramatic upper body adipose hyperplasia due to a missense mutation in mitofusin 2, involved in mitochondrial fusion and other processes. Physiological, tissue and cellular studies of humans and mouse models will address the role of DNA replication/repair and mitochondrial dynamics in depot-specific human adipose remodelling, and will test both mitigating strategies and relevance for common disease. The second part of the project will exploit emerging techniques for saturation mutagenesis coupled to downstream functional assays to develop "look up" tools for stratification of genetic variants by functional consequence. Saturating mutation libraries and such derived tools have myriad applications, including genetic diagnosis of rare disease, patient stratification for experimental medicine studies, and linking of functional perturbations to lifecourse human phenotypes in genotyped cohorts. The approach will be applied first to the insulin receptor, and thence other genes involved in insulin signal transduction.

Amount: £1,883,117
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The Sick of the Fringe Business Development 30 Sep 2018

Support costs for The Sick of the Fringe to develop a rigorous 3-year core business plan.

Amount: £50,000
Funder: The Wellcome Trust
Recipient: Sick of the Fringe Ltd

Regulation of CD25 expression and IBD risk 31 May 2018

The inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disorders of the gastrointestinal tract affecting 1 in 400 people in the UK. Both have a complex aetiology involving genetic predisposition and environmental triggers which is not yet fully understood, but may result in persistent bacterial infection, defective mucosal barrier, or a dysregulated immune response. Genome-wide association scans (GWAS) have identified over 200 IBD-associated loci (Lui et al 2015). One locus encompasses the gene encoding the IL-2 receptor alpha chain (CD25). CD25 is expressed by activated T cells and important in signalling pathways that regulate the immune response. Our fine-mapping data (Huang et al 2017) show that the GWAS signal at IL2RA/CD25 is due to a single SNP associated with CD, in intron 1 of the gene and co-localising with a super enhancer that regulates expression (Fahr et al 2015). This SNP is also associated with Type 1 diabetes and multiple other autoimmune disorders. In this study we will identify additional recently recruited IBD patients who are homozygous for the CD risk allele at this SNP by genotyping and investigate alteration in the expression of IL2RA by qPCR in flow-sorted regulatory and effector T cells.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Adult-Neurogenesis and Network Remodeling on Zebrafish Telencephalon 04 Dec 2017

Zebrafish exhibits adult neurogenesis throughout their brain, conferring them the amazing ability to regenerate damaged brain regions. The study of network remodeling by adult neurogenesis involves complex relationships between newly-added neurons, preexisting networks, and neuronal activity. This proposal combines my expertise on adult-neurogenesis and information processing, the zebrafish capability to perform network remodeling, and the available genetic tools to label different zebrafish neuronal types, as: progenitors, glutammatergic and GABAergic neurons. By combining these transgenic fishes with BrdU tracing, molecular marker detection and electrophysiology, we will able to perform a rigorous and elegant characterization of the different neuronal repertoire contributed by adult neurogenesis to telencephalic pallial networks. Furthermore, the impact of cognitive function on network remodeling will be tested by in vivo two-photon Ca2+ imaging on different cohorts of new-neurons. This project will be the seed for further research on functional neuronal regeneration and de novo wiring of pallial regions, assessed by the physiological and behavioral recovering of lesioned brain.

Transforming Research Management in Africa 30 Sep 2018

This application seeks funding for salary support for the Research Systems Manager (RSM) at The African Academy of Sciences for two years and a series of activities for one year that will inform a larger Programme of Work on "Transforming Research Management in Africa". Further funding will be sought after this period. The initial activities are; UK Visit: Allen Mukhwana, RSM, visited the UK 1 – 17 March. She visited the Wellcome for orientation and met with potential co-funders and partners. Stakeholder Consultative meeting: A meeting was held in Nairobi on 8th and 9th February to discuss the Programme. Baseline Survey: to assess capacities across African institutions to inform interventions. Engagement with Deputy Vice Chancellors in Addis Ababa: RSM attended this meeting. H3Africa Inception meeting, Entebbe 20 - 23 March: RSM will attend to promote the Programme. INORMS: 25 research managers will participate in the International Network of Research Management Societies meeting in Edinburgh 3 – 8 June 2018. Site support visits: to work with the managers to improve their research environment and management. DELTAS Africa Annual General Meeting: promote Programme 6-11 July. Programme Development & Networking opportunities: RSM will attend the regional associations (RIMAs) meetings/conferences to promote the Programme.

Amount: £209,603
Funder: The Wellcome Trust
Recipient: African Academy of Sciences

Reprogramming the epigenome: erasing memory and creating diversity 10 Apr 2018

Epigenetic memory needs to be globally reprogrammed in the early mammalian embryo for cells to attain broad developmental potency including naïve pluripotency. Exit from pluripotency in turn requires rapid establishment of epigenetic memory in the form of epigenetic priming. This involves both ‘activating priming’ whereby lineage specific genes are protected from repressive marking to safeguard their future transcriptional activation during tissue and organ development, and ‘repressive priming’ by which genes of a different lineage are suppressed. These large-scale dynamics raise fundamental questions about the impact of epigenetic memory on pluripotency and differentiation, which we address in this research programme. First, we will attempt to disable global demethylation in vitro and in vivo by manipulating the epigenetic coordinator UHRF1 at the transcriptional and posttranscriptional levels. Second, using genetic and epigenetic manipulation we will determine the mechanisms and downstream consequences on lineage and tissue development of ‘activating priming’ factors we have recently identified. Third, we will investigate the role and targets of ‘repressive priming’ and epigenetic heterogeneity in cell fate decisions and lineage development. New insights gained into memory erasure and epigenetic determinants of cell fate will illuminate and guide strategies for using ES, iPS, and multipotent stem cells in regenerative medicine.

Amount: £2,634,297
Funder: The Wellcome Trust
Recipient: Babraham Institute

The Genetic Basis of Congenital Hypothyroidism 30 Sep 2018

I have already identified 2 novel genetic causal variants for congenital hypothyroidism (CH) by whole exome sequencing (WES); IGSF1 defects in central hypothyroidism and SLC26A7 in dyshormonogenetic CH. I will therefore continue this strategy to identify further genetic causes of CH. I will expand my CH cohort, enriched for probability of genetic mutations. After excluding candidate gene defects, cases will undergo WES. I will then undertake functional characterization of specific novel variant s using in vitro techniques and a zebrafish model of thyroid development. Human SLC26A7 mutations are a novel cause of dyshormonogenetic CH and the disorder or its pathogenesis has not been characterized; I will phenotype cases to define this syndrome in more detail. I will characterize the biological function of SLC26A7 (a key transport protein), by performing electrophysiological studies to define its role as a putative anion transporter in the thyroid. Structure-function relationships in S LC26A7 are poorly understood. I will therefore characterize the properties of naturally-occurring and artificial SLC26A7 mutants to define functional domains in this protein.

Amount: £214,297
Funder: The Wellcome Trust
Recipient: University of Cambridge

Sustained release of drug-loaded nanoparticles from a novel vaginal ring design 31 May 2018

Sustained-release drug products are useful in prolonging the action of a drug in the body by maintaining therapeutic concentrations of the drug over extended time periods. Here, we are particularly interested in polymeric vaginal rings for long-acting vaginal administration of drugs (1). Various steroid-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and a new ring device – developed in part by the Queen's University Belfast (QUB) and offering sustained release of the antiretroviral drug dapivirine for HIV prevention – is due to reach market soon. However, a major limitation of current vaginal ring technologies is that they are generally not useful for administration of either large molecule drugs or drug-loaded nanoparticles, due to limited solubility and/or diffusion in the polymeric materials used to manufacture rings. Here, we propose for the first time to test a novel vaginal ring developed at QUB for sustained release of drug-loaded nanoparticles, with potential applications in prevention/treatment of sexually transmitted infections, mucosal immunisation, and treatment of cervicovaginal cancers. The ring device comprises orifices in the ring surface which expose the underlying drug-loaded core. The ring is easy to manufacture using highly-scalable and conventional injection molding technologies.

Amount: £0
Funder: The Wellcome Trust
Recipient: Queen's University Belfast

Design and Synthesis of a Bifunctional Linker for generating Haptenated Flagellin Bioconjugates for Improving Vaccine Reach and Lifespan 31 May 2018

The protein, flagellin, has been shown to enhance vaccine responses in systemic and mucosal sites, and bolster long-lived Ab responses. The ability of flagellin to migrate to mucosa opens up a strategy for delivering other antigens to the gut mucosa to elicit a more robust immune response, which is desirable for a vaccine to maximise its potential to protect. Activated iNKT-cells elicit potent systemic IgG responses but their ability to modulate mucosal antibody responses, including IgA, is less clear. If we could administer iNKT-cell agonists systemically in a way that ensures they reach mucosal sites, we would be able to examine this in depth. We now propose to use flagellin–iNKT-cell agonist conjugates to do just this, by employing flagellin as a carrier to deliver iNKT-cell antigens to the mucosa and in so doing, hopefully induce a robust mucosal antibody response. This Summer research project will focus on the synthesis of a bifunctional molecule which we will use to attach a potent iNKT-cell glycolipid agonist, which we have previously assembled, and then use the second functionality to conjugate the iNKT-cell agonist to the flagellin molecule selectively through surface-exposed Tyr residues that are concentrated in the hypervariable region of the flagellin molecule.

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

Investigation of epithelial differentiation in a mouse wound model 31 May 2018

Lipoxygenase (LOX) enzymes are expressed by infiltrating immune cells and are involved in innate immune and inflammatory response, all of which are fundamental processes in wound healing. The overarching aims of this larger body of work is to evaluate the role of 12/15-LOX in the cellular orchestration of wound healing using a murine model. We have induced full thickness (4mm) wounds in wildtype and 12/15-LOX knockout mice, then measured wound closure rates and harvested skin tissue at various time points post wounding and conducted histological evaluation of skin sections. Our initial data has found that in 12/15-LOX knockout skin there is enhanced fibroblast expansion, and a reduced infiltration of macrophages, both of which might be beneficial in chronic wound states where failure in fibroblast proliferation and an overt inflammatory state occur. However chronic wounds also displays deficits in wound re-epithelialisation and given that 12/15-LOX products can inhibit epidermal hyperplasia (by modulating cyclin/CDK signalling), we believe that KO mice might also display an enhanced re-epithelialisation phenotype. Therefore, to test this hypothesis we will explore the rate of re-epithelialisation and the cytokeratin profile of epithelial keratinocytes in KO and wildtype mice at various time points post wounding.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Regulation of microglial phagocytosis 30 Sep 2018

Microglia are the brain's immune cells. They constantly survey the brain to search for invading micro-organisms, unwanted molecules (such as amyloid plaques in Alzheimer's disease) or dying cells, but also play a key role in sculpting the circuitry of the brain by removing unnecessary cells and synapses during development. The mechanisms by which microglia constantly move their processes to survey the brain, and then remove invading micro-organisms, plaques, cells or synapses, are poorly understood. I will use 2-photon and confocal imaging techniques to investigate these events, taking advantage of recent discoveries from the Attwell lab which have revealed the importance of microglial potassium channels and purinergic receptors in controlling these events.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

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

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. 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.

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

Resolving mesodermal diversification with single cell transcriptomics 30 Sep 2018

During the course of development, cells divide, migrate, and specialize to form major organ systems. Furthemore, among most mammals and birds, mouse cells differentiation follows a unique morphology. Understanding the molecular mechanisms underlying such process is a core issue in Biology and a curiosity in mouse, which despite differences still share fundamental properties during the process. The challenge has been addressed by leveraging current high-throughput technologies such as single cell transcriptomics. The amount and complexity of this data requires innovative mathematical frameworks that take advantage of current computational capacities. I am intersted on resolving mesodermal diversification during mouse gastrulation. Based on the premise that single cell profiles represent snapshot measurements of expression as cells traverse a differentiation process, I will use probabilistic modeling among other statistical and mathematical methodologies to reconstruct a measure of a cell’s progression through some biological process, and to model how cells undergo some fate decision and branch into two or more distinct cell types. In particular, Bayesian Inference has shown to be a useful approach to take advantage of computational resources, and to include prior knowledge into models, by providing a formal probabilistic framework that allows learning from the data in order to make predictions.

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

Synthesis and Antichagastic Evaluation of Novel Drug Scaffolds 31 May 2018

Neglected Tropical Diseases (NTDs) affect more than one billion people per year and have a severe impact on the economy of developing countries. This threat is heightened for communities affected by poverty, poor sanitary infrastructure and contact with transmission vectors or infected livestock. Chagas disease, part of the NTDs is a potentially life-threatening disease caused by Trypanosoma cruzi parasites, and is commonly spread by infected triatomine bugs. Up to 10 million people are estimated to be infected worldwide, predominantly in endemic countries such as Latin America but the disease is spreading to non-disease endemic locations such as Europe, the United States of America and Canada. Benznidazole and Nifurtimox are the only approved medicines for use by the World Health Organisation but these drugs are ineffective in treating the chronic phase of the disease and have potentially fatal side-effects. Dr Bhambra’s research group has identified a novel drug scaffold displaying antichagastic activities whist remaining non-toxic to mammalian cells. Therefore, this scholarship will include the design, syntheses and safety screening of further novel compounds with drug-like properties, and aim to deliver molecules with greater on-target potency and reduced off-target effects leading to promising compounds suitable for further preclinical investigation.

Amount: £0
Funder: The Wellcome Trust
Recipient: De Montfort University

Reaching TB elimination: the use of emerging technologies for TB control in high burden settings 30 Sep 2018

Tuberculosis (TB) is a leading cause of death as an infectious disease. Recent surveillance data from India has revealed the TB epidemic to be larger than expected. Although TB incidence is decreasing, the End TB Strategy of reducing TB incidence by 90% by 2035 is unlikely to be met with current control measures that predominantly target patients with active TB disease. In order to help reach the End TB Strategy goals, new tools to reduce TB incidence and mortality are needed. These tools can target different stages along the TB health care cascade. For example, tools can be developed to prevent non-infectious latent infections turning into infectious active disease, or tools can be developed to reduce the amount of time infectious individuals spend in the community. I will use transmission-dynamic models to explore the potential impact of emerging technologies on TB in Southeast Asia, a high TB burden region. These studies will help determine the optimum use of new and emerging technologies for TB control, as well as what the investment priorities are for high burden settings, such as India.

Amount: £0
Funder: The Wellcome Trust
Recipient: Imperial College London

Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018

Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

ROS via RET: a redox regulated pathway to extend lifespan 17 Jul 2018

Reactive Oxygen Species (ROS) play a dual role in cellular physiology. On one hand, ROS are damaging oxidants that have been proposed to cause ageing. On the other, ROS are essential messengers required for maintaining cellular homeostasis. The aged and sick accumulate defective mitochondria that generate high levels of ROS, but antioxidant therapies fail to improve prognosis or extend lifespan. Furthermore, increasing mitochondrial ROS levels in animals extends lifespan rather than reducing it. A new paradigm explains these contradictory results proposing that under normal physiological conditions, ROS are only produced at specific sites (e.g. mitochondria) by specific ROS generators (e.g. respiratory complex I) which regulate distinct redox signalling pathways. Conversely under pathological conditions ROS are produced at unspecific places causing oxidative stress. My laboratory has characterized the first site-specific ROS signalling pathway which regulates animal lifespan: ROS produced via reverse electron transport (RET) at respiratory complex I. This proposal will fully characterize this new redox signalling pathway by addressing three aims: (i) identify the genes and proteins involved in the initiation, amplification and neutralization of ROS-RET, (ii) understand when and where ROS-RET needs to be activated to extend lifespan, and (iii) dissect the pathological consequences of dysregulation of ROS-RET signalling.

Amount: £1,512,586
Funder: The Wellcome Trust
Recipient: Newcastle University