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Results

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

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

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

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

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

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

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

The role of Fubp3 in the pathogenesis of osteoporosis 30 Sep 2018

Osteoporosis is the commonest disease of bone. Affected individuals have an increased risk of fracture as bone is of reduced strength and quality. Fractures can cause significant pain and disability as well as costs to the health service. The number of people with osteoporosis is increasing as the population gets older. Currently treatments are limited, but understanding the genetics of bone disease has already led to promising new treatment ideas. Genetic studies of large numbers of people have associated variants in Fubp3 with both osteoporosis and fractures. However, FUBP3 is not currently known to have a function in bone. We hypothesise that it may be required for normal bone growth and maintenance of normal bone mineralisation and strength. We will study mice lacking the Fubp3 gene in order to understand the function of FUBP3 in bone. With this knowledge we hope to identify new signalling pathways involved in osteoporosis which can be targeted by new treatments.

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

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £21,050
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Dissecting the role of aryl hydrocarbon receptor in thermogenic adipose tissue 06 Jun 2018

The obesity crisis has reached epidemic proportions and represents one of the most significant global public health challenges. The recent discovery of energy dissipating brown adipose tissue (BAT) in adult humans has raised the possibility of targeting BAT for the treatment of obesity. Indeed, studies in humans and mice have demonstrated an inverse relationship of BAT activity with obesity and metabolic syndrome. I propose to explore the potential of natural dietary compounds that are sensed by the aryl hydrocarbon receptor (AHR) as novel inducers of BAT activity. I will identify the physiological role of AHR in thermogenesis and utilize conditional gene-targeting approaches to define cell-autonomous functions of AHR in specific cell-types within BAT. Importantly, I will determine whether dietary AHR ligands, such as phytochemicals and microbiota metabolites, can induce the thermogenic activity of BAT, promote energy expenditure and improve metabolic disease in the context of obesity. To elucidate the mechanisms by which AHR modulates thermogenic programs, I will identify its direct transcriptional targets in specific cell-types using ChIP-seq and RNA-seq. Together, these studies will provide important insights into the regulation of thermogenesis by specific dietary factors and may facilitate the use of natural AHR ligands for the treatment of obesity.

Amount: £1,286,093
Funder: The Wellcome Trust
Recipient: Imperial College London

How curiosity enhances hippocampus-dependent memory 06 Jun 2018

In today’s world, it is most desirable to optimize cognitive capacities, such as learning, across the lifespan. One fundamental, yet poorly understood, method is via a person’s intrinsic curiosity. Despite the ubiquity and importance of curiosity in everyday life, we have a very limited appreciation of the exact neural mechanisms of curiosity-enhanced learning. Because initial curiosity studies have relied on the passive encoding of material, one fundamental aspect of curiosity – active exploration to acquire further knowledge – remains to be investigated. I, therefore, propose a new virtual reality paradigm to characterize the neural mechanisms of how active curiosity enhances memory. Across three principal approaches, I will ask how separate stages of memory (orientation vs. initial learning vs. different modes of consolidation) contribute to curiosity-related memory enhancements and why curiosity-based learning might vary between healthy individuals. I will uncover whole-brain mechanisms and ‘zoom in’ on specific curiosity- and memory-related brain structures using complementary state-of-the-art measures and analyses. Combining such approaches is vital if we are to understand how curiosity enhances memory, but may also aid crucial translation of laboratory-based findings on learning and memory to real-world issues (e.g., influence on educational policies and implications for cognitive resilience in the elderly).

Amount: £959,155
Funder: The Wellcome Trust
Recipient: Cardiff University

A modern cryo-EM facility at Imperial College London 05 Jul 2018

Cryo-electron microscopy (cryoEM) is becoming the major tool in elucidating the inner workings of cellular machines. In 1997, Imperial College London, with help from the Wellcome Trust, established the first cryoEM facility dedicated to single particle work in the UK and, through the continuing support of WT, has been an international leading player and centre of excellence in cryoEM. Our current user community has benefited tremendously from this excellent facility. However, equipment in the facility, especially for grid preparation and handling, is in urgent need of upgrading or refurbishment, and is insufficient in capacity. With the successful award of a Titan Krios from the WT (LonCEM) and access to national resources (eBIC), the focus of our facility is shifting from data collection to sample preparation, screening and preliminary data generation. We therefore request funds to upgrade our facilities in terms of grid preparation and screening to maintain competitiveness and embrace new technology development. The proposed upgrades will transform the throughput and quality of our sample preparation providing a state of the art capability allowing us to make optimal use of the LonCEM Krios facility when that comes online (late 2018) as well as other national (eBIC) and international resources.

Amount: £197,672
Funder: The Wellcome Trust
Recipient: Imperial College London

Identifying the pathogenic triggers of CD8 T-cells in multiple sclerosis . 13 Nov 2014

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), affecting 2.5 million individuals worldwide. Treatments are available, but are complicated by side effects and variable response profiles. There is an urgent need to define the pathogenesis of MS and design novel therapeutics. There is evidence that CD8 T-cells play a major role in the pathogenesis of MS. Studies also suggest a role for herpes viruses in MS, however, it remains unclear what triggers di sease. My preliminary data demonstrates that CSF resident T-cells have an antigen-driven phenotype. T-cell receptor (TCR) usage in the CSF resident CD8 T-cell repertoire is highly skewed with a restricted number of dominant TCRs. I hypothesize that a viral infection, such as EBV, triggers CD8 T-cells, which subsequently target and damage host cells. Here, I intend to identify the pathogenic triggers of dominant CSF-resident T-cells, thereby elucidating the aetiology of this debilitating disease. Specific aims: 1. To perform an in-depth phenotypic analysis of T-cell populations in the CSF of MS patients. 2. To identify dominant CSF resident TCRs in MS patients. 3. To define the pathogenic triggers of dominant CSF-resident TCRs.

Amount: £173,892
Funder: The Wellcome Trust
Recipient: Cardiff University

Direct recording of mechano-electrical transduction currents and forces from individual stereocilia. 30 Apr 2015

Mechano-electrical transduction (MET) in the inner ear occurs when a sound's energy is transmitted to MET channels in the hair-cell stereocilia. Channels' gating and stereocilia motion are directly and reciprocally coupled. This mechanical coupling involves tip links--molecular springs whose tension determines the channels' open probability. Pulling on a tip link opens a channel; channel opening relaxes the spring. This relaxation, called gating compliance, involves channel motions exceeding a d ozen nanometres, astoundingly large for an ion channel. Classical models posit one MET channel connected to a tip link's upper end. Recent experiments reveal instead two channels at a tip link's lower end. No model today can explain the number and location of the MET channels, nor how the large gating compliance, necessary for sensitive hearing, occurs. I propose that adjacent MET channels are energetically coupled through elastic deformations they create in the lipid bilayer, and that they ther efore open and close cooperatively. Large gating compliance arises naturally in my model, provided the channels are at the tip link's lower end. To quantify the MET-channel cooperativity and the associated gating compliance requires new methods: single-stereocilia patch clamp and single-tip-link microrheology. This collaborative project's objective is to develop these methods.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Homeostatic plasticity and the maintenance of neural dynamics in a changing world: converging theoretical and experimental approaches. 19 Nov 2014

Recent experimental work provides suggests that spontaneous activity of the brain is organised as an approximately critical system with the dynamics of the system in an attractor state between order and disorder. In many natural examples of critical dynamics, critical activity is maintained for only a small range of environmental conditions according to a tuning parameter, dependent on specific aspects of the organisation of the system (e.g., network topology). How the brain maintains and explo its critical dynamics over a range of diverse environments (homeostasis) is unclear; however, theoretical work suggests that some form of synaptic plasticity is likely to be an important mechanism for tuning critical neural dynamics [9,10]. The key goals of this fellowship will be to combine dynamic mean field computational models [11-13] with models of homeostatic plasticity based on excitatory/inhibitory balance [14,15] to show how criticality can be maintained with a changing environment. The model will be evaluated against existing functional neuroimaging data and electrophysiological datasets, during environmental change (both over short and long time scales). This data will allow assessment of model predictions at multiple temporal and spatial scales.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Epidemic dynamics of pathogenic human enteroviruses. 19 Nov 2014

I aim to identify the mechanisms determining the epidemic dynamics of serotype-specific human enterovirus (HEV). I will use mathematical and statistical models to examine epidemiological and microbiological data collected since 2003 as part of ongoing enterovirus surveillance in the UK and the US. In particular, I will assess the importance of birth rates, serotype-specific population immunity, cross-immunity between serotypes, and climatic and environmental factors. I will use time-series an alysis to test relationships between climatic and environmental factors and HEV disease incidence, and correlation in the incidence of different serotypes over time and space. I will then develop mathematical models representing alternative hypotheses that can explain the patterns of disease occurrence. Mechanisms likely to result in the observed dynamics, such as serotype-specific and heterotypic immunity and seasonal determinants of transmission efficiency will be included. I will fit these models to HEV disease incidence using recently developed statistical methods, and estimate model parameters, including the degree and duration of homotypic and heterotypic immunity. Finally, I will examine whether available viral sequence data is consistent with patterns of diversity predicted by these mathematical models and use phylodynamic methods to see whether these data allow more accurate estimation of model parameters.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Landscapes of Health: The Black Sea in the Socialist World. 25 Nov 2014

Landscapes of Health: The Black Sea in the Socialist World is a workshop with two main objectives. First, it seeks to develop our understanding of the role of Black Sea health resorts in socialist medical theory, practice, and culture. It highlights the importance of the sea, rest, environmental health, and natural healing to socialist ideas and practices of health. The workshop develops the idea of the Black Sea coastline of socialist Bulgaria, Romania and the Soviet Union as a shared zone of h ealth in the geography of the socialist world. Second, the workshop develops the idea of health resorts as international meeting places. The workshop marks the 70th anniversary of the Yalta conference (February 4-11, 1945), and brings to light the role of medicine and socialist ideas of health in Cold War diplomacy. Health resorts were showcases of the socialist world, in a Cold War contest fought publicly over welfare and standards of living. This workshop brings together for the first time scholars studying the health resorts of the Black Sea, with contributions from specialists in the history of medicine, history, film, architecture and urban planning, and scholars of both the Soviet Union and the Eastern Bloc.

Amount: £4,900
Funder: The Wellcome Trust
Recipient: Birkbeck University of London