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Results

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

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

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

Chronic suppurative lung disease (CSLD) in children - Characterisation of a tertiary hospital cohort 31 May 2018

Chronic suppurative lung disease (CSLD) in children is a broad term including a range of lung diseases of different aetiologies characterised by intense neutrophilic inflammation, chronic productive cough, poor airway clearance and progressive lung injury with increased risk of recurrent infections. Robust epidemiological data on children with CSLD is sparse globally. There are also no long-term prospective studies in children to guide clinical care and management into adolescence and adulthood. Indeed, guidelines for management of paediatric CSLD are usually based on expert opinion alone. This project aims at identifying and characterising a cohort of children aged

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

Mapping the targets of RNase MRP 30 Sep 2018

Cartilage hair hypoplasia, or CHH, is an uncommon disease. Patients with this disease have short limbs and thin hair. They also have problems with their immune system, making them vulnerable to infections. These patients have a mutation in their DNA, in a gene called RMRP. In healthy people, we think RMRP helps build ribosomes. Ribosomes are the cell’s factories which turn the instructions in DNA into the proteins which make up the body. But this happens in all cells, and so it is hard to understand why people with CHH only have problems with their bones and immune system, while most other organs work well. Understanding this is a first step to thinking about new treatments. We will use recently developed techniques to map all the molecules in the cell which interact with RMRP. We will initially apply these in yeast cells, which are similar to human cells, and in human cells grown in the laboratory. We will then determine what happens when we introduce the DNA changes seen in patients into these cells, and into a laboratory mouse strain. This will give us a better understanding of how RMRP normally works, and what goes wrong in the patients.

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

Thinking forward through the past: Linking science, social science and the humanities to inform the sustainable reduction of endemic disease in British livestock farming 30 Jan 2018

Livestock disease today is a complex and pressing problem that threatens the development of more sustainable, ethical and efficient farming methods. This project will devise a fundamentally new approach to its investigation that advances understandings and informs responses. Cutting across the traditionally separate realms of nature and culture, science and society, human and animal, and past, present and future, experts in veterinary history, environmental economics, epidemiological modelling, human and animal geography, rural sociology and cultural history will work collaboratively across six institutions, and in close conjunction with stakeholders to investigate two major endemic health problems: Bovine Viral Diarrhoea in cattle, and lameness in cattle and sheep. Experiences of these problems in Britain since 1947 will be examined within four contrasting farming systems - upland and lowland ‘beef and sheep’, and indoor and pasture-based ‘dairy’ – to reveal how perceptions of, and responses to disease co-evolved with farming systems and communities, human-animal relationships, expert knowledge-practices, consumer attitudes, and wider political, economic and cultural contexts. Findings will inform - and be informed by - the development of epi-economic models that better predict the future incidence of, and farmer responses to disease, generating suggestions for how to mitigate its effects.

Amount: £218,525
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Vulnerability and justice in global health emergency regulation: developing future ethical models 30 Nov 2017

The Award will support the foundation of a network of academics, with the aim of developing proof-of-principle that ethical models and guidelines on global health emergencies (GHEs) can be better attuned to concerns of vulnerability and justice. The network will enable a step-change in the scholarship on vulnerability and justice in GHEs. GHEs, in this context, are defined as crises that affect health, and are (or should be) of international concern (e.g. epidemics and pandemics, health in conflicts or mass migration). Collaborators will explore strategies to increase the ethical robustness of future regulation across challenging events, using futures-studies methods. Ultimately this project will lead to a larger grant application using similar methodology and vision. Key goals: To contribute to conceptual and applied knowledge on the connection between vulnerability and justice in the context of GHEs (defining key concepts, identify gaps) To co-design with knowledge users (policy makers, humanitarian actors), ethical models and strategies for a futures-oriented approach to the regulation of GHEs. To develop scholarship, expertise and collaborations in view of a larger grant application (based on the vision that future GHE regulation and ethics can be better attuned to concerns of vulnerability and justice, using a futures-oriented approach)

Amount: £66,060
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Carbonyl Reductase 1 and 20β-Dihydrocortisol: a novel glucocorticoid metabolism pathway in the pathogenesis of mineralcorticoid activation in obesity. 25 May 2017

Dysregulation of the balance of corticosteroid action via glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) contributes to inflammation, cardiovascular and metabolic disease. I have discovered a novel pathway of cortisol metabolism by the cytosolic enzyme carbonyl reductase 1 (CBR1) producing 20beta-dihydrocortisol (20beta-DHF), a weak agonist of glucocorticoid receptor (GR) but a potent mineralocorticoid receptor (MR) agonist. I have shown that CBR1/20beta-DHF is up-regulated in obesity, specifically in adipose, in humans and animals. In obese mice, CBR1 inhibition enhanced hepatic GR signalling (associated with greater glucose intolerance) but reduced renal MR signalling. I hypothesise that up-regulation of CBR1 in obesity leads to increased MR activation, contributing to hypertension and adipose dysfunction. To test this hypothesis I will generate an in vitro model with independent GR- and MR-responsive reporters and test the effects of CBR1. I will determine MR binding and downstream effects of 20beta-DHF in vivo; test the effects of global Cbr1 knockout and adipose-specific Cbr1 overexpression on MR activation in murine obesity.

Amount: £477,201
Funder: The Wellcome Trust
Recipient: University of Edinburgh

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

Institutional Translation Partnership Award: Robotic Surgery 30 Sep 2017

Surgical robotics is an ever-expanding area of innovation and development internationally, spearheading evolution in precision medicine. Access to increasingly small and remote anatomies, characterisation of cellular and molecular information in-situ, in-vivo, and targeted therapy with increased precision are major drivers of the future generation of surgical robots. The purpose of this partnership is to capitalise on the timely evolution in the imaging, sensing and robotics research programmes currently being conducted within the Hamlyn Centre for Robotic Surgery and to address research and clinical translational challenges of precision surgery, focusing on knowledge transfer between academic research, industry, and clinical practice. Through a pioneering new model of academic translation, this partnership will stimulate Imperial's multidisciplinary academic community in surgical robotics, driving the progression of a portfolio of new medical engineering products

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Large population 2-photon imaging and targeted optogenetics in the mouse primary visual cortex during the acquisition of a visually-guided learning task 05 Dec 2016

Large population 2-photon imaging and targeted optogenetics in the mouse primary visual cortex during the acquisition of a visually-guided learning task

Amount: £79,108
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Role of ATP in Chronic Cough 11 Jul 2017

The cough reflex is triggered by ion channels present on vagal nerve termini which can be activated by a wide variety of irritants. Utilising a P2X3 antagonist we have identified ATP as a driver of chronic idiopathic cough which is treatment refractory. However, the mechanisms are not known and it is not clear whether similar efficacy will be observed in chronic cough associated with common respiratory diseases. We have identified different neurophenotypes in patients with chronic cough associated with different lung diseases suggesting that a single therapeutic may not address cough across all indications and that mechanistic information will be required. Furthermore, upstream targets, involved in the release of ATP, may provide a broader efficacy profile as ATP has been shown to have a range of disease relevant biological effects in the lung mediated by purinoceptors. We will identify (1) whether ATP is a biomarker of treament sensitivity; (2) upstream targets involved in the release of ATP; (3) the contribution of the upper airway to ATP-induced sensations; (4) the role of ATP in mediating chronic cough across other airway diseases? This project will identify novel targets, biomarkers and the patient phenotypes that will respond to treatment.

Amount: £1,506,732
Funder: The Wellcome Trust
Recipient: Imperial College London

The retention of memory and creation of knowledge 11 Jul 2017

Memories are often formed automatically, selectively retained and then some information becomes incorporated into the networks of knowledge that each of us possess. A key challenge is to identify the neural mechanisms responsible for the selective retention of recent hippocampal-dependent memory traces and those mediating the incorporation of this information into existing knowledge networks in the neocortex. Phase 1 concerns selectivity: Guided by predictions of the synaptic-tagging-and-capture hypothesis of protein synthesis-dependent memory consolidation, we would use a novel everyday-memory task to follow up our observations that certain parameters of learning, including peri-event novelty, enhance memory retention. Experiments using genetically modified animals that involve neurotransmitter imaging and endoscopic Ca2+ imaging would explore the potentially critical role of a neural circuit from the locus coeruleus to the hippocampus in selective retention. Phase 2 addresses knowledge assimilation: This work would be conducted in the context of the new schema theory of semantic-like memory that presupposes that prior knowledge guides memory updating. It would follow up our original experiments on schema learning, introduce a new method for doing such experiments, explore endoscopic imaging in both hippocampus and neocortex, and the network contributions of distinct neocortical regions using a disconnection approach.

Amount: £1,660,214
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Mechanisms of how endocrine hormones regulate appetite 31 May 2018

The aim of this project is to investigate whether specific metabolites produced in the duodenum during digestion and correlated with the release of the gastrointestinal hormone glucagon-like peptide-1 (GLP-1) actually drive this release of GLP-1 to regulate energy and glucose homeostasis. We will use gut organoids as a model of enteroendocrine cell function to study the effects of the metabolites tyrosine, taurine and acetone, alone and in combination, and with or without glucose present. Hypothesis: Tyrosine, taurine and acetone will stimulate GLP-1 release from duodenal organoids Aim: To investigate the effects of tyrosine, taurine and acetone on GLP-1 release Objective: To establish whether tyrosine, taurine and acetone alone or in combination with each other or glucose stimulate GLP-1 release from duodenal organoids This work will establish the possible role of these metabolites in driving GLP-1 release, and thus whether using them as dietary supplements may represent a potential therapeutic approach to obesity and metabolic disease.

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

PhD Grant Proposal 30 Sep 2018

Older people are often classed as either experiencing ‘normal’ cognitive ageing, or ‘pathological’ cognitive ageing as a result of diseases such as Alzheimer’s (AD). However, these classifications fail to reflect the spectrum of cognitive decline that is experienced as we age. Age-related cognitive decline is a hugely important health problem; it has a profound impact on quality of life, increases the risk of depression and may herald dementia. Because of this, it is important to investigate what influences how well we age cognitively. Age itself is the biggest risk factor for cognitive decline. The comprehensive causes and mechanisms of ageing are not fully understood but we do know that the process is closely integrated with inflammation – the body’s immune response to injury or irritants. Although recently receiving significant attention, the precise cause-and-effect relationship between inflammation and cognitive ageing has not yet been fully explored. Using different techniques, this project will investigate the role of inflammation in cognitive ageing, and whether the process can explain why some people are more resilient than others. Understanding the differences in individual’s cognitive decline is critical to developing interventions to prolong cognitive health and to gain insight into diseases of cognition such as AD.

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

Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo 31 May 2018

Title: Developmental gene expression profiling for novel mediators of epithelial fusion in the chick embryo. Hypothesis: Tissue fusion processes in vertebrates are essential for normal embryonic development. Novel factors recently identified in our lab using transcriptome profiling during epithelial fusion within the embryonic chick eye may have roles in fusion in additional embryonic contexts. We will perform whole mount in situ hybridization for the genes NTN1, FLRT3, CYP1B1 and RGMB using chicken embryos at key fusion stages in the developing neural tube, body wall and heart. These analyses will inform us whether the protein products of these genes are required for fusion in these tissues. Uniquely in the chicken embryo, the palatal shelves do not fuse. Therefore, identification of continual gene expression in the developing non-fusing palate will also help to identify which of these factors may act to prevent fusion. Data will be collected and analysed using brightfield microscopy and optical projection tomography (OPT). Key goals: (i) Establish spatial gene expression profiles for four genes between chick embryonic stages HH16-26; (ii) determine those genes with conserved roles in fusion for multiple tissues; (iii) categorize genes into likelihood of promotion or inhibition of tissue fusion.

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

Characterizing transcriptional transition states in cell differentiation 30 Sep 2018

As stem cells differentiate, their transcription profiles change over time. These complex dynamics are essential for generating specialised cell types and facilitating normal development. I aim to characterise the movement of these differentiating cells through gene expression space using a multidisciplinary approach. I will use stochastic models to simulate stem cell dynamics over developmental time, and fit these models to transcriptomic data using Bayesian methods (Approximate Bayesian Computation and Particle Markov Chain Monte Carlo). My approach also aims to incorporate structural information from Genome Architecture Mapping experiments, to further improve these models. This work will improve the characterisation of key transition states within stem cell dynamics, and lead to more informative models of cell differentiation.

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

Decoding adaptive immunity: high-throughput sequencing and characterisation of the immune repertoires produced during parasitic infections 30 Sep 2018

Despite extensive research, there remains no effective vaccine licensed for any human parasitic infections. This has been attributed to a lack of knowledge available regarding the development of naturally acquired immunity to such infections. Following pathogen exposure, clonal expansion of T and B-cells occurs, generating repertoires of lymphocytes that are a distinct response to the pathogen. High-throughput sequencing, in combination with proteomics, now provides the opportunity to study these immune responses in precise detail, delineating components of protective immunity and identifying their critical antigenic targets, providing unparalleled insights in to the mechanisms underlying immunity to a pathogen. By sequencing T and B-cell repertoires produced during parasitic infections, we aim to document conserved T cell and antibody responses that convey protection, and identify what antigens they are targeting, to inform vaccine design. Key goals are to provide proof of principle for this approach using a controlled animal-model of the malaria parasite Plasmodium chabaudi, before analysing human acquired immunity in Schistosomiasis. We aim to document TCR and antibody sequences that are elicited during immune responses to these parasitic infections, identify conserved ‘public’ antibody signatures generated and characterise their antigenic targets, thereby addressing the key knowledge gaps that have precluded effective vaccine design.

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

Statistical Analysis of the Type 6 Secretion System in Pseudomonas Aeruginosa 30 Sep 2018

Pseudomonas aeruginosa is a Gram-negative bacterium that is a leading cause of many hospital borne infections. In particular recent research has identified the Type 6 Secretion System (T6SS) present in P. aeruginosa and has focused on the structure and mechanism of the system. This highly complex system allows P. aeruginosa to accurately penetrate adjacent cells and thus insert an array of toxins which can cause cell death or disrupt cellular pathways. Building on this work we would like to understand the T6SS from a statistical perspective. Understanding the spatial distribution and dynamics of the T6SS along the cell membrane of P. aeruginosa are amongst a number of different questions we hope to explore in this project. To achieve these targets we will use fluorescently tagged components of the T6SS mechanism as well as confocal microscopy of living P. aeruginosa, thus allowing for 3-dimensional reconstruction. These biological questions will be answered using a variaty of quantitative approaches. To extract important information from the image data a number of imaging and video preprocessing methods will need to be applied. After preprocessing the this data will be analysed using a variaty of statistical methdologies in order to provide a quantitative description.

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

Investigation of pro-regenerative mesenchymal subpopulations during liver regeneration using a single cell RNA sequencing approach 30 Sep 2018

Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. The liver has a remarkable ability to regenerate following injury, however in many cases of CLD this regenerative capacity is overwhelmed. Currently the only effective treatment is liver transplantation but demand for donor organs greatly outstrips supply. New therapies are urgently required. Liver regeneration involves a complex interplay between multiple cell types, including a family of cells called mesenchymal cells. Whilst traditionally, the role of mesenchymal cells was more often studied in the context of liver fibrosis (scarring), recent studies have shown that these cells are also important during liver regeneration. Initial experiments in the Henderson lab, using a cutting-edge technology called single cell RNA sequencing (which allows the sequencing of genes in single cells), has shown that mesenchymal cells, rather than being one family of cells with similar function, are actually very varied in terms of their function, performing many different, important roles within the liver. I will use this powerful technique to identify the pro-regenerative mesenchymal cell subpopulations responsible for driving liver regeneration. Using this information, we hope to design new treatments to harness specific cellular subsets to drive liver regeneration in patients with CLD.

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