- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 25 Jan 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
" Transcranial magnetic stimulation (TMS) is a rapidly developing non-invasive technique for studying human brain functions and for therapeutic applications nevertheless, the precise mechanisms of TMS activation is still poorly understood. The aim of this project is to explore the underlying physiological processes that are activated by TMS in the primary motor cortex (M1), as paradigmatic activation for other brain areas. TMS in M1 was shown in the past to evoke several different motor outputs, d epending on the direction of the induced current in the brain and the waveform of the stimulating current (also known as the D-I waves phenomenon of the motor evoked potentials). The project will use a novel experimental approach that combines TMS with a cell type specific optogenetic interrogations and a state-of-the-art fluorescent imaging to explore the effect of the induced fields directly within the magnetically excited tissue of an animal model. The outcomes of the project will impact t he design of new investigation procedures and the development of new TMS diagnostic and therapeutic strategies with better specificity. The conclusions of this project will improve our understanding of the cortical processes involve in the motor control and will help to establish the safety boundaries of TMS. "
Information transmission through cross-frequency coupling: revealing the frequency structure of information exchange in the brain. 12 Jan 2015
Could there be a structure to information flow through the brain, with different brain areas workingat particular temporal resolutions? Moreover, what type of information is communicated from areato area in the brain? More specifically, which frequency bands are employed by the different brainareas to convey information to each other? While high frequencies (gamma frequency range) mayplay an important role in local computations early on in the cortical hierarchy, the rhythmicactivity of attention (theta frequency range) may act to gate information flow to higher order areasin the frontal lobe, effectively acting as a filter which allows only particular packets of informationunto the stage of our everyday consciousness.
Background: Several intracellular pathogens escape from phagosomes and reach the host cytosol where they can polymerize actin, leading to motility and cell-to-cell spread. However, only a small fraction of intracytosolic bacteria form actin tails, and a complete understanding of the molecular events restricting bacterial dissemination has not been obtained. Objectives: Using Shigella flexneri I will pursue the following aims: (1) To identify and characterize host and pathogen determinants un derlying the intracellular fate of cytosolic bacteria; (2) To investigate the role of discovered molecules and mechanisms in vivo using new experimental models of infection. Expected results: Completion of these objectives will provide insights into the mechanisms required for the control of infection by cytosolic host responses.
Institutional Strategic Support Fund 2013/14 14 Oct 2013
Antimicrobial Research Collaborative (ARC) Fellowships The Antimicrobial Research Collaborative (ARC) is a new Imperial network of researchers, primary care specialists and allied health professionals established to advance basic research in Antimicrobial Research (AMR) and to translate research to novel prevention strategies and healthcare interventions. More information can be found on the ARC website [http://www.imperial.ac.uk/arc]. The ARC Early Career Research Fellowships scheme aims to attract and retain the most promising early career scientists to undertake multidisciplinary research projects in AMR within the College. Whilst funding is available to support any research within the remit of AMR, proposals addressing interdisciplinary research in the following strategic priority areas are particularly encouraged: Health Services and Policy; Health Economics; Microbiologyand the Environment. 1-Year Clinical Training Fellowships in Global Health Research - Open We are looking to support outstanding early-career clinical professionals wishing to undertake research, at least in part overseas, to improve the health of people and reduce health inequalities in developed and developing countries. Through the provision of clinical training fellowships in global health, we aim to provide opportunities for the most promising clinical academics, at the very beginning of their careers, to develop bids for independent fellowship funding. We anticipate that each fellow will be supported by two mentors, one based at an Imperial Campus, and one based overseas Value in People - Open VIP awards must be used within the broad aims of assisting Imperial College in the recruitment, career progression and retention of new academic and research staff that are key to the implementation of the university’s strategic objectives in the area of biomedical science. The proposed work must be within the remit of the Wellcome Trust and the applicant must have formally submitted an application for at least 2 years further support to an external funding body. In the academic year 2014-15 we would particularly welcome applications for bridging support (for PDRAs and fellows) and short-term support for non-biologists who wish to experience working the biomedical field. Networks of Excellence - Open The purpose of this scheme is to foster novel, interdisciplinary biomedical research endeavours across the Faculties of Medicine, Engineering, Natural Sciences and the Business School. Therefore the College welcomes proposals which offer greater collaboration across disciplines, departments and/or institutions. Proposals for pilot or feasibility work for high risk projects, to support collaborative cohesion, test or develop new methods, or proof of concept studies are encouraged, rather than standard projects. It is envisaged that the outcomes of this work will form the basis of a major grant application. Whilst funding is available to support any research within the remit of the Wellcome Trust [http://www.wellcome.ac.uk/Our-vision/index.htm], proposals addressing interdisciplinary research in Biomedical Engineering, Global Health and Development (including Epidemiology, Prevention and Control) and Infection Research (including Antimicrobial Strategies & Resistance) are particularly encouraged.
FILM microscopy facility: New generation confocal and high content screening microscopes, and upgrades for intravital microscopy. 25 Jun 2014
For the systematic investigation of contextual physiological information, we request a High-content screening (HCS) microscope with confocal fluorescence capacity. FILM already supports experimental upscaling and data analysis of HCS screens performed elsewhere, but increased capacity and direct access to a confocal HCS system are urgently needed. FILM has an outstanding track record in intravital microscopy, but a major limitation is currently detector sensitivity and multiphoton laser power . We therefore request an upgrade of the intravital microscope with hybrid detectors and DeepSee laser to increase imaging depth. Several users perform research on the effects of mechanical cell stress. The Flexcell system would allow microscopic measurements under controlled conditions including the imaging of fluorescence biosensors which readout the intracellular signalling consequences of mechanical strain. FILM embeds leading-edge technologies into a full support system offering acces s to a large range of high-end microscopy technologies. Some of our microscopes are outdated with regard to speed and sensitivity, we therefore request funds to replace one ageing confocal by a new-generation system. All these technologies critically depend on expert support, and the multisite nature of Imperial College makes constant support difficult. We request an additional support staff position to cope with increased and distributed demand.
Investigating the diversity, molecular epidemiology, competitive influence and therapeutic potential of pneumococcal bacteriocins using large genome datasets 05 Apr 2017
Genomics has revolutionised infectious disease research. The rapidly growing volume of genomic data allows unprecedented depth and breadth of discovery. High quality genome sequence data from well-sampled studies are advancing our understanding of fundamental aspects of microbiology, epidemiology, population biology and microbial evolution. My group is among those at the forefront of this change: e.g. we recently published an analysis of 5,405 pneumococcal genomes. Five years ago this was impossible. My research is focused on Streptococcus pneumoniae (the ‘pneumococcus’), a leading global pathogen. My particular recent focus is bacteriocins – antimicrobials produced by bacteria to kill other bacteria. We analysed ~350 pneumococcal genomes for evidence of one type of bacteriocin cassette associated with niche competition and discovered that all pneumococci maintained this cassette and that it was genetically highly diverse. Surprisingly, one-third of the genomes also possessed genes encoding either a novel circular bacteriocin or a lantibiotic bacteriocin. Subsequently, we identified >10 novel bacteriocins among ~500 pneumococcal genomes, a much higher frequency than expected. Why do pneumococci possess so many different bacteriocins? Using large genome datasets, we will provide an unprecedented, highly-detailed investigation of pneumococcal bacteriocins and assess their potential as novel antibiotics.