- Total grants
- Total funders
- Total recipients
- Earliest award date
- 27 Apr 2000
- Latest award date
- 30 Sep 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Volunteering Matters 06 Nov 2014
Piloting Engage and Transform, a scheme to break down cultural barriers and develop a long-term partnership of mutual benefit between public and social sector organisations.
Since December 2019 the emergence of severe acute respiratory infections (COVID-19) in China, caused by the new coronavirus SARS-CoV-2, has posed a huge threat to global health with fatality rates up to 10% in elderly patients. Almost 100% of patients showed bilateral patchy shadows or ground glass opacity in their lungs by chest CT scans indicating acute lung injury (ALI). Therefore, understanding the underlying mechanism(s) of ALI induced by SARS-CoV-2 is very important to inform vaccine safety and immunotherapeutic strategies. In this proposal, we will investigate the host immune responses and their association with severity of ALI in patient samples and animal models. We will bring together a team of experts with complementary expertise including immunopathology in coronavirus infections, up-to-date lab technologies, and know-how to ensure the feasibility of this study with the following goals: 1) defining SARS-CoV-2 specific serum profiles (epitopes) using yeast display antigen library 2) determining antibody functions including antibody-dependent enhancement (ADE) vs neutralizing activities in vitro assays 3) studying T cell (CD4 and CD8) responses to whole SARS-CoV-2 genome 4) evaluating ALI in response to live SARS-CoV-2 infection with or without passive immunity (antibody or T cells) generated from vaccine candidates in a humanized mice model.
Neuro-immune-stromal pathways sense environmental change to regulate repair versus remodelling during airway disease 31 Mar 2020
This application will test the hypothesis that pulmonary immune homeostasis is maintained by a network of tissue resident cells that continually monitor environmental change. Disruption of local neuro-immune-stromal interactions either by genetic or environmental factors, alters the threshold for immune responses to usually innocuous particles such as dust, pollen or dander leading to chronic airway inflammation and tissue remodelling. I will ascertain the cellular and molecular composition of the airway wall parenchyma in children and adults with severe asthma and use machine learning tools and mouse models to determine the impact on lung function. Viral infection and pollution are common triggers for asthma severity, and I will establish how the immune/stromal niche communicates with the external environment to react to these inhaled stimuli, focussing on interaction with neuronal systems. I will examine how these interactions differ in severe asthma and contribute to the ensuing inflammation, remodelling and lung dysfunction. I will investigate the cellular interactions between fibroblasts, extracellular matrix and type 2 immune cells that facilitate repair versus remodelling during severe asthma. Ultimately this programme will reveal insight into mechanisms underlying tissue remodelling versus repair during severe asthma.
A search-engine inspired platform enabling open sharing and access of both data and results from all genomic studies 16 Oct 2019
Large amounts of public and charity money have been spent on genomic studies. In non-model organisms, which make up over half of all available sequence data, sharing falls far short of the standards of democratisation and dissemination that funders and researchers envisage. Common issues include paywalled publications, needing to repeat expensive basic data processing steps, and difficulty even finding data. Overcoming these issues requires significant amounts of time, expertise and computational resources. A combination of inflexible database services, lack of advanced methods, and high hurdles to sharing published analyses have collectively led to this situation. Innovative solutions are desperately needed. We will link datasets with inherently variable structures, searchable with new indexing tools and a novel ranking algorithm to make these invaluable scientific resources truly open. We will adapt technology used in the highly successful strategy employed by search engines, which index, rank and deliver results from billions of webpages which have no unified structure. Our new tool will allow users to search for sequences or other biological features, and group results by samples, species or projects. Results will be ordered by relevance, linked to downloads of published data and visualisations, and further enhanced with analysis performed by the tool itself. Both web and programmatic interfaces will be available. Our solution’s flexibility, relaxing almost all format requirements imposed by databases on researchers, will lead to broad uptake. Many research communities will benefit (microbiology, immunology, bioinformatics, LMICs and public health), and we anticipate starting to shift open research practices within genomics.
Genomic and functional characterisation of cell-type specific epigenetic and genetic mechanisms implicated in human obesity. 05 Dec 2019
Regulation of gene expression by DNA methylation (5mC) in response to genetic and environmental risk factors is considered important to human obesity and type-2 diabetes (T2D) pathogenesis. Yet, difficulty finding causal 5mC changes in humans is limiting downstream clinical applications. I have discovered 5mC changes robustly associated with obesity and their predicted effector genes in human adipocytes. I have then refined these loci and genes using human genomics, cross-species transcriptomics and biological evidence to 3 top candidates for discovery of novel mechanisms of disease – the MEDAG, FGFRL1 and TXNRD1 loci. I will use sophisticated gene targeting to investigate the causal effects of the MEDAG, FGFRL1 and TXNRD1 genes on obesity and T2D in a mouse model of human disease, and detailed phenotyping to examine the pathophysiological mechanisms. In parallel, I will use functional and experimental genomics to explore the regulatory significance of obesity-associated 5mC sites on MEDAG, FGFRL1 and TXNRD1 gene expression, and the underlying epigenetic mechanisms, in human adipocytes. These complementary lines of evidence will establish whether locus-specific 5mC variations and subsequent gene expression changes impact on human obesity phenotypes, and may define epigenomic and molecular targets for new obesity and T2D therapies.
While emerging antimicrobial resistance is widely recognised in bacteria, the emergence of fungi that are resistant to antifungal drugs is underappreciated yet is compromising our ability to treat these serious diseases worldwide. The most widely used class of chemicals, the azoles, are driving the evolution of fungal multidrug resistance through their dual-use in both agricultural and clinical settings. However, we lack critical insights into how these antifungal chemicals are leading to changing patterns of disease in humans. We focus on Aspergillus fumigatus, an environmental fungus to which all humans are exposed causing disease in millions, and which is rapidly evolving resistance to azole antifungal drugs worldwide. Our project aims to understand the risk that azole-resistant aspergillosis presents to public health by identifying the extent to which patients are acquiring resistant infections from environmental sources. We will explore whether the emerging spectrum of mutations that confer drug resistance come with a fitness cost, how these mutations impact upon the global population of A. fumigatus with respect to undesirable phenotypes such as virulence and infectivity. The science that our study produces will be focused on tackling this pandemic in order to retain the efficacy of essential current, and incoming, clinical antifungal drugs.
Multicellular organisms use systemic signals to transmit biological information across tissues in order to co-ordinate responses to stress or infection. Discovering such signals, how they spread and what responses they trigger is therefore of paramount importance for organismal development. We have previously introduced the first tractable animal system to investigate a diverse group of eukaryotic pathogens, the oomycetes, which cause deadly infections in humans, as well as the model organism Caenorhabditis elegans. We have now discovered that C. elegans is able to sense these pathogens in neurons and mount a protective transcriptional response, the hallmark of which is the induction of conserved chitinase-like proteins in its epidermis. We propose to use comprehensive molecular genetics, cell biology, biochemistry, metabolomics and developmental imaging to determine the host response underlying pathogen recognition and elucidate the molecular gene network underlying the mounting of this response via neuron-to-epidermis signal exchange. Studying intercellular signalling requires a system-wide approach and, to this end, C. elegans offers a great opportunity to investigate this fundamental problem at the whole organism level. The proposed work will expand our knowledge on core cell and developmental biology mechanisms of intercellular signal exchange and immune response in the context of oomycete recognition.
Disentangling serotype diversity and the corresponding patterns of immunity in Streptococcus pyogenes 06 Nov 2019
Group A Streptococcus (GAS) causes a wide range of diseases, from pharyngitis and scarlet fever to potentially fatal invasive disease. GAS bacteria can be subdivided into serotypes (emm-types), grouped in emm-clusters. The existence of serotype-specific immunity following infection is established, however the extent of cross-strain protection, has not been measured. Using a combination of longitudinal cohort, surveillance and genomic data, I will use transmission-dynamic modelling and learn genomic analysis to infer the protective efficacy of naturally acquired immunity to GAS, including the extent of type-specific and heterotypic immunity. I will identify whether there is a biological basis for emm-cluster-level immunity – including whether emm-types predicted to produce immune cross-reactivity map to genetic similarity, or exhibit similarities in horizontally-acquired non-emm antigens. I will analyse the evolutionary epidemiological dynamics of GAS, to determine whether patterns of emm-type and emm-cluster prevalence over time can be explained by demographic replacement of susceptible individuals, or immune escape via pathogen evolution. The results of these analyses will allow me to inform key public health questions, including predicting the population-level impact of introducing a test-and-treat strategy for pharyngitis in UK children, and predicting the impact of polyvalent incomplete vaccines on antibiotic consumption in a US setting.
The role of post-synaptic GPCR intracellular trafficking and signalling on synaptic plasticity 06 Nov 2019
G protein-coupled receptors (GPCRs) are the largest family of signalling receptors, regulating a variety of cellular functions including neurogenesis and synaptogenesis. Therefore, GPCRs are the main pharmaceutical targets, however, the lack of knowledge regarding the association between neuroplasticity and GPCR function makes them an underexploited target for neurodegeneration. GPCR signalling activity is regulated via their trafficking to intracellular compartments, namely endosomes. Membrane trafficking of neuronal receptors is an established mechanism in the regulation of synaptic plasticity, especially in those areas of the brain involved in learning and memory (e.g. hippocampus), although the molecular mechanisms and its link with signalling remain poorly understood. Using beta-adrenergic receptors (BARs) as prototype GPCRs, we aim to target this knowledge gap by 1) identifying BAR trafficking pathways in hippocampal neurons; 2) generating a map of BAR signalling along their endosomal trafficking; 3) determining the role of BAR spatially encoded signalling on synaptic plasticity. Through the development of novel approaches to study the local organization of synapses, this project will help to understand how GPCR activity can be modulated via targeting receptors to defined cellular locations in the hippocampal neuron and specifically within individual synapses, offering the potential for novel GPCR-based therapeutic targets for neurodegeneration.
Neural induction is the process responsible for the generation of the entire nervous system. A major question in the field is how this process results in the production of diverse cell types throughout the nervous system, and how it can be applied to regenerative medicine. I recently showed that CDX transcription factors are critical to establish spinal cord fate, but that their capacity to induce spinal cord is lost following neural lineage commitment. Moreover, my preliminary data suggests that CDX factors broadly impact posterior identity in cells, prior to germ layer segregation, that is critical for the generation of different neural subtypes in the nervous system in vivo. In this proposal, the key goals are to: investigate the regulatory mechanisms limiting Cdx2 expression in cells; evaluate how CDX2 represses alternative brainstem fates for the generation of spinal cord; and test the role of CDX in the divergence of neural cells, including neural crest cells, that form distinct fates within the nervous system, in vivo. Taken together, this work will provide molecular insight into how cellular diversity is established in the mammalian nervous system and more generally throughout the body plan.
Collaborative Award in Science, ‘SouthEast Asian Research Collaboration in Hepatitis (SEARCH)’ 26 Nov 2019
An estimated 1.07 million people in Vietnam are infected with hepatitis C virus (HCV). In the ‘VIETNARMS’ trial, we are investigating the efficacy of HCV treatment strategies that could be used to treat underserved populations (e.g. ultrashort or intermittent therapy). Should these strategies have efficacy as hoped, it will be crucial to develop innovative ways to engage with underserved populations. We propose a ‘bottom up’ approach using community based participatory research (CBPR) to explore barriers to HCV care and to determine what actions must be taken to improve engagement with these populations at risk for HCV. In this project, we will first conduct stakeholder mapping of organizations working with populations at risk for HCV and create two advisory groups, one at the NGO level and the second at the community level. Next, we will conduct CBPR with 3-5 communities in Ho Chi Minh City over the course of one year. Using CBPR methods, we will work with communities to identify barriers, facilitators, and health priorities related to HCV, as well as design and implement strategies to overcome the problems identified in each group. We will hold dissemination meetings in the communities where CBPR took place, with the local advisory groups, and with regional stakeholders to determine how to integrate dialogues from underserved communities at risk for HCV into larger policy conversations centering on HCV care and treatment. The questions raised and strategies implemented in the communities could also inform future operational research questions within our context.
<p style="margin-left: 0cm; margin-right: 0cm">The Carbohydrate Microarray Facility at Imperial is an internationally leading operation providing collaborations for discoveries of glycan ligands to the biomedical community (<u>http://www.imperial.ac.uk/glycosciences/)</u>. Data accrued are making significant contributions to understanding the involvement of specific glycans in health, infections, inflammation, immune responses and cancer. <br> <br> This unique collaborative way of serving the community, with follow-through of data from screening analyses, has enabled substantial advances to be made in glycobiology.<br> Access to ample amounts of glycans that is often required to corroborate assignments from screening analyses has largely depended so far on external collaborations with chemists. New links that we are forging with the Department of Chemistry to provide desired glycans are of fundamental value for the future of the Facility. <br> <br> We are seeking 4 years support to further integrate the new era of glycomics into biology and medicine. We will</p> <ol> <li>develop a unique human epithelial mucin/O-glycome resource for diverse recognition studies, in particular microbe-host interactions.</li> <li>expand the ‘glycosaminoglycome’ and brain ‘gangliome’ library.</li> <li>complement and diversify the library of glycan sequences with chemically and chemo-enzymatically synthesized glycans, guided from glycan array data.</li> <li>introduce new software for integrated data management and data mining of glycome array analyses.</li> </ol>
Enhancement, dissemination and application of the PhyreRisk/Phyre resource for modelling protein structures and the effects of genetic variants 04 Jul 2019
<p>We are applying to support the enhancement, dissemination and application of the PhyreRisk/Phyre resource. PhyreRisk ( http://phyrerisk.bc.ic.ac.uk ) caters for researchers studying human genetic variation. Through PhyreRisk, a user can map DNA variants, from either genomic or proteomic coordinates, onto experimental and Phyre-predicted protein structures. The Phyre web-server (www.sbg.bio.ic.ac.uk/phyre2<u> </u>) is a widely-used (>90,000 distinct users in 2018) ELIXIR-UK resource to predict protein structure from sequence. Additionally, our program Missense3D (<u>http://www.sbg.bio.ic.ac.uk/~missense3d/</u> ) provides structure-based evidence for the effect of a missense variant.</p> <p><br> Funding will be used to develop the following new predictive features within Phyre for subsequent inclusion in PhyreRisk:<br> (i) prediction of ligand/protein interactions,<br> (ii) template-free tertiary structure prediction using contacts<br> (iii) domain/domain packing.</p> <p><br> PhyreRisk will be markedly extended by:<br> (i) increased structural coverage from Phyre and predicted complexes from our collaborator in Kansas<br> (ii) enhancing Missense3D to include functional residues, protein/protein interactions and membrane-bound proteins to yield quantitative predictions<br> (iii) the inclusion and subsequent analysis using Missense3D of genetic variants reported in major databases (e.g. gnomAD, ClinVar, COSMIC, Genomics England and UK-BioBank). <br> (iv) linking PhyreRisk, particularly the structural data, to other resources including gnomAD.</p> <p><br> We will disseminate the resource via workshops, conference presentations and publications.</p>
<p style="margin-left: 0cm; margin-right: 0cm">Arboviral diseases caused by arthropod-borne viruses and their complications constitute a major challenge for public health in Brazil, as they are currently spreading widely and are expanding in geographic regions that are presently outside transmission zones. We will consider two mosquito-borne diseases: dengue and chikungunya, and we will focus on quantitative spatio-temporal methods for studying the interrelations between climate, disease distribution and environmental conditions and the synchrony that these systems express. By taking advantage of multiple data sources, we will develop a hierarchical spatio-temporal approach grounded within a Bayesian framework with the following key goals: (i) to examine the spatial distribution and temporal dynamics of arboviral diseases in relationship to climatological factors, in presence of changes in the local environmental conditions, (ii) to predict the probability of outbreak of the diseases in space through time with quantified uncertainty. We will consider also other relevant factors for disease transmission such as demographic characteristics of the population. This project not only will provide new epidemiological insights into the ongoing debate about the interaction between global changes and arboviral disease epidemics, but also will produce methodological advances that in turn will yield operational inputs for strengthen early warning systems, optimizing dedicated resources.</p>
<p>Epigenetic reprogramming and transcription have been thoroughly studied in primordial germ cells (PGC). However, an unexplored aspect is the role of core-promoters in regulation and execution of this program. It was recently discovered that thousands of promoters undergo a change in basic rules for transcription start site (TSS) selection between maternal/oocyte and zygotic/somatic transcription, effectively switching from one overlapping promoter architecture to another upon zygotic genome activation. This also implies that there should be a switch in the opposite direction during germline development, but when and how this happens is unknown, along with how it affects genome regulation and organization.</p> <p><br> Here, we set to investigate TSS usage during mouse PGC differentiation and oogenesis using our low-input methodology for mapping TSSs. Specifically, we aim to: 1) capture the developmental stage and epigenetic context in which the TSS-switching occurs; 2) uncover the underlying regulatory mechanisms. Since we believe that comparative studies are powerful for revealing general rules of animal development, opposed to lineage-specific innovations, we shall take advantage of collaborations to expand the study to zebrafish and Drosophila. Long-term, we expect that our results will provide better understanding of PGCs and gametes and lead to more efficient <em>in vitro</em> specification protocols.</p>
<p>I aim to identify the mechanisms driving the emergence of enterovirus serotypes as a new cause of disease and their spatio-temporal patterns of spread using multiple data streams and mathematical and statistical models.</p> <p>First, I will study the extent to which serotype-specific immunity explains the cyclical incidence of enteroviruses causing hand-foot-and-mouth disease, both by fitting transmission models to incidence data and exploring correlations with estimates of population immunity from serosurveys. Second, using cross-sectional seroprevalence and virus sequence data I will explore how gaps in population immunity and virus genotypic and phenotypic changes have led to the recent emergence of two new serotypes causing diseases (EV-D68 and CV-A6) following periods of low incidence of cases. Third, using phylogenetic and phylogeographic methods, I will characterise the geographical range of spread and global and regional patterns of viral movement of the three currently most important serotypes (EV-A71, EV-D68 and CV-A6), and I will explore how human mobility and other predictors drive these spatial patterns.</p> <p>Understanding the mechanisms underlying the epidemiological dynamics of enteroviruses will help prioritise strategies to mitigate the morbidity associated to these infections by informing the serotypes that should be targeted by future vaccines, and optimise outbreak control and vaccination strategies.</p>