- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Epigenetic memory needs to be globally reprogrammed in the early mammalian embryo for cells to attain broad developmental potency including naïve pluripotency. Exit from pluripotency in turn requires rapid establishment of epigenetic memory in the form of epigenetic priming. This involves both ‘activating priming’ whereby lineage specific genes are protected from repressive marking to safeguard their future transcriptional activation during tissue and organ development, and ‘repressive priming’ by which genes of a different lineage are suppressed. These large-scale dynamics raise fundamental questions about the impact of epigenetic memory on pluripotency and differentiation, which we address in this research programme. First, we will attempt to disable global demethylation in vitro and in vivo by manipulating the epigenetic coordinator UHRF1 at the transcriptional and posttranscriptional levels. Second, using genetic and epigenetic manipulation we will determine the mechanisms and downstream consequences on lineage and tissue development of ‘activating priming’ factors we have recently identified. Third, we will investigate the role and targets of ‘repressive priming’ and epigenetic heterogeneity in cell fate decisions and lineage development. New insights gained into memory erasure and epigenetic determinants of cell fate will illuminate and guide strategies for using ES, iPS, and multipotent stem cells in regenerative medicine.
Following the 2015 oral cholera vaccine (OCV) mass campaign of 160,000 people in Nsanje District, Malawi, the International Vaccine Institute (IVI) was funded to setup diarrheal disease surveillance in Nsanje and adjacent Chikwawa districts. Surveillance is ongoing at 22 and 18 health care facilitiesin Nsanje and Chikwawa, respectively. Research activities include to 1) analyse the vaccine effectiveness (VE) in Nsanje, through a 1:4 case-control study and 2) conduct a cost-of-illness study to help estimate OCV cost-effectiveness. The IVI is working in parallel in neighboring Mozambique. Diarrheal disease surveillance is ongoing in the Cuamba study area and an OCV has been conducted in 08/2018. The Mozambique study area borders the Malawian Nsanje/Chikwawa districts. We propose to continue the research in Malawi through extending the surveillance work and the case-control study, to ensure the assessment of long-term VE and cost-effectiveness. Further, the extent of herd protection through OCV needs to be assessed; the Chikwawa setting, after the 2018 OCV campaign constitutes the perfect scenario. The GFTCC is currently preparing a research agenda for "End cholera by 2030" roadmap and the Malawi/Mozambique scenario with surveillance ongoing in both countries, provides an unique opportunity to answer research questions identified through the GFTCC.
Thymic epithelial cells (TEC) avert autoimmunity through their ability to promiscuously express virtually the entire protein-coding gene repertoire as a molecular library against which immature T cells are selected. An integrative analysis of the transcriptome, epigenome and proteome of distinct TEC subpopulations will be used to attain an unparalleled systems-level understanding of the molecular conditions that select a tolerant T cell repertoire under normal physiological conditions. Establish ing the molecular mirror of tissue specific self-antigen expression by single TEC has implications for understanding autoimmunity, the design of vaccines and the formation of a repertoire of tissue-specific regulatory T cells that can be co-opted by tumours to escape from immunological detection. Our findings will also be relevant for other areas of biology where stochasticity in gene expression of individual cells (e.g. stem cells) influences the establishment and maintenance of cell fate and function, and where gene silencing is overcome either as part of regular developmental programmes or in the context of malignant transformation. To achieve these aims we will develop generally useful new proteomic and microfluidic methods, single cell genomic and epigenetic technologies, novel mathematical models of cellular interaction, and new statistical approaches for understanding biology at single cell resolution.
Characterization of novel E3 ubiquitin ligases that are enriched in LGR5-positive intestinal stem cells and niche. 03 Oct 2015
In the intestine, LGR5-positive (LGR5+) crypt base columnar cells comprise a well-defined adult stem cell population. FACS isolation of LGR5-positive intestinal stem cells have facilitated the expression profiling of LGR5+ stem cells, which established stem cell-specific genes of the adult intestine. Amongst are two homologous E3 ubiquitin ligases, RNF43 and ZNRF3, the inactivation of which resulted in unrestricted expansion of intestinal stem cells and formation of adenomas due to hyper-activat ion of Wnt signalling. This has started uncovering the importance of E3 ligases in regulating intestinal stem cells. Besides RNF43 and ZNRF3, additional uncharacterized E3 ubiquitin ligases are enriched in intestinal stem cells. By using cell-surface marker CD24 to sort and profile Paneth cells, novel additional E3 ubiquitin ligases were also detected in these niche cells. These novel E3 ubiquitin ligases are the focus of this research plan, since it is anticipated that they play an important ro le in stem cells, niche cells and their interaction. The plan includes: 1) Functional screening of candidate E3s using primary 3D intestinal organoid culture; 2) Identifying target proteins of candidate E3s using surface proteome analysis and IP-MS; and 3) Validating the role of candidate E3s using mouse genetics in vivo.
The role of IFITM-mediated restriction of HIV-1 entry in acute infection and viral tropism 08 Jun 2015
Human Immunodeficiency Viruses must avoid host innate and adaptive immune responses that restrict their replication in vivo. This is in part achieved through the action of several viral accessory gene products. The HIV-1 Vpu protein counteracts the antiviral activity of the interferon-induced membrane protein Tetherin, which inhibits the release of diverse enveloped viruses from infected cells. We will use virological, biochemical and microscopy-based studies to understand the molecular and cell ular basis of how Vpu and other viral proteins subvert the trafficking of tetherin to prevent its incorporation into assembling virions, and to identify and characterize the cellular proteins required for these processes. Tetherin is not the only target of HIV-1 Vpu. We have used isotope labelling of plasma membrane proteins to identify a novel Vpu target, TOV3, a glutamine transporter. TOV3 is essential for proliferation of activated CD4+ T-cells raising the possibility that Vpu modulates T-cel l function by limiting glutamine availability. We will determine how Vpu-mediated TOV3 targeting affects viral replication and proliferation/survival of infected T-cells and macrophages to understand how this activity might contribute to HIV-1 pathogenesis. We will also adapt the isotope labelling to identify further targets of HIV-1 Vpu and Nef in HIV-1 infected primary cells
Prenatal Assessment of Genomes and Exomes (PAGE) 25 Apr 2013
Women have ultrasound scans of their baby in pregnancy to check for structural abnormalities (such as a heart defect). If a problem is found, women are offered prenatal testing to check for chromosomal abnormalities in the baby, such as Down’s syndrome. This helps to predict the outcome for the child.The chromosomes in our cells consist of strands of DNA which encode all the genes. Standard genetic testing detects large chromosomal changes that can be seen down a microscope. In some centres additional testing can detect smaller chromosomal changes. Dr Matthew Hurles at the Wellcome Trust Sanger Institute and colleagues plan to look in the greatest possible detail, down to the level of individual building blocks of DNA, to examine the genes. In this study, as the amount of information generated by this testing is vast and the interpretation time-consuming, results cannot be given during the pregnancy. If a genetic reason for the abnormal scan findings is found, this information would be given to parents after pregnancy. This could provide important information about the health of the child or implications for future pregnancies. This research will allow the team to discover new genes responsible for causing abnormalities and, if appropriate, to develop methods for speedy feedback of important information during pregnancy in the future.
Exploring the biological processes underlying mutational signatures identified in cancers. 20 Nov 2012
Somatic mutations in cancer genomes have been generated by multiple DNA damage processes, the effects of which may have been mitigated by the cellular repertoire of DNA repair mechanisms. Each process will leave a characteristic imprint, or mutational signature, on the cancer genome. Our understanding of these signatures and their underlying mutational processes is remarkably limited. The overarching theme of this proposal is to explore the biological basis of mutational signatures that emerge f rom sequencing whole cancer genomes. The first aim is to systematically manipulate components of the DNA repair/replicative machinery in model systems, by targeted disruption or over-expression, followed by re-sequencing of clones to define genome-wide mutational signatures generated by these engineered abnormalities. The second main aim is to establish a resource of induced pluripotent stem cells (iPSCs) and/or lymphoblastoid cell lines (LCLs) from patients with naturally occurring germline defects in genes involved in DNA repair/replication to study mutational patterns in these patients. Thirdly, the large projected datasets generated from these experiments will require computationally demanding exploration and downstream analyses. Ultimately, experimentally generated datasets will be compared to mutational signatures extracted from large-scale sequencing of cancer genomes, giving us insight into the perturbations that happen during cancer development.
We will exploit the opportunities of the UK National Health Service to generate a national resource of human iPS cells and associated data. We will generate and bank lines from 700 healthy and 800 disease-associated individuals, optimising techniques for iPS cell production and quality control. Cells will be subjected to extensive analysis of genome, epigenome, gene expression and proteome. For cells from healthy individuals, in-depth analysis of inter-individual variability will provide an open access platform for association studies of cellular function, and for distinguishing pathological from physiological variation. Patient collections will be selected via an open call, focusing initially on well-characterised conditions, where a single genetic lesion underlies a pleiotropic clinical phenotype. To characterise cellular phenotype we will construct high throughput artificial microenvironments. We will evaluate cell death, differentiation, morphology and division and specific signall ing pathways. We will collaborate to produce protocols to differentiate iPS cells into disease-relevant cell types. These approaches will provide in vitro readouts of inter-individual variation and disease and a platform for gene correction and engineering specific mutations into different genetic backgrounds. Our proposal will give researchers in the UK and beyond access to iPS cells and technology linked to extensive genetic, cellular and clinical information.
Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses 08 Apr 2013
The aryl hydrocarbon receptor (AhR), a ligand dependent transcription factor best known for mediating the toxic effects of xenobiotics, has recently been shown to play important roles in the immune system, although mechanistic insight is lacking. AhR is expressed in a wide range of haematopoietic cells, but also on epithelial cells interfacing with the environment, eg skin, lung, intestine. We plan to investigate the physiological functions of AhR in the immune system by generating AhR-FTAP mice to identify protein interactions with AhR in different cells types and immunological conditions to gain mechanistic insight into how AhR works. Furthermore, we will focus on the physiological regulation of AhR signaling via metabolic enzymes such as CYP1A1 that are induced by AhR activation and subsequently metabolise the agonist in a negative feedback loop. Mice with targeted deletion of the three CYP enzymes under control of AhR show increased AhR stimulation and have a range of immunological phenotypes, which we plan to explore, using infection/inflammation models targeting skin, lung or intestine. AhR deficient mice on the other hand show hyperinflammatory reactions, suggesting that interference with the regulation of AhR activation adversely affect homeostasis at these barrier sites. Analysis of mice with cell type specific AhR deletion will identify cell intrinsic consequences of defective AhR signalling. We furthermore plan to generate mice overexpressing CYP1A1 to test the hyp othesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barriers sites.
DNA in all cells is prone to mutagenesis, with somatic mutations making key contributions to human diseases such as cancer and neurodegenerative diseases, and to aging itself. Mutations are the consequence of exogenous or endogenous mutagenic influences (including radiations and DNA-damaging chemicals) and also result from enzymatic DNA modifications or low fidelity DNA synthesis by specialized DNA polymerases. Mutations are generally prevented by the cellular DNA-repair machinery and defective functioning of this machinery can markedly increase mutation rates. Different mutational processes leave different, characteristic signatures of somatic mutations on the exposed cellular genome. Notably, recent analyses of cancer genomes have revealed several novel mutational signatures, the biological bases of which are predominantly unknown. To define somatic mutational processes operative in cells, and in particular their influences on human disease, we propose to systematically survey, at th e genome-wide level, mutational signatures generated by exposures to known or putative human carcinogens, defective DNA repair/editing processes or dysfunction of other cellular processes. These studies will provide a set of mutational signatures with known underlying causes for subsequent matching to signatures found in normal or diseased human cells and will expand our knowledge of how various cellular components influence mutagenesis.
Karonga Prevention Study (KPS) : whole genome sequencing in a whole population: supplementary proposal for tuberculosis whole genome sequencing 30 Nov 2011
HIV, tuberculosis and pneumococcal disease are leading causes of mortality and morbidity in Africa. They interact, and undermine development. Control measures exist but are inadequate (HIV, tuberculosis) or unproven (pneumococcus). By combining the established large-scale Karonga epidemiological studies and knowledge of long-term disease trends with detailed laboratory and genomic analysis we will: 1. measure pneumococcal carriage, transmission and serotype change at a household level fo llowing pneumococcal conjugate vaccine (PCV) introduction into the EPI schedule, trial alternate PCV schedules, and determine options to maximise vaccine benefits using modelling methods. 2. identify where M.tuberculosis is being transmitted by screening patients at antiretroviral clinics, by tuberculin testing and by defining transmission chains using whole genome sequencing, to target control efforts. 3. establish genomic determinants of virulence in M.tuberculosis by comparing s trains that have transmitted and caused disease with those that have not, and investigate long term non-progression of latent infection to better understand the host and pathogen determinants of M.tuberculosis natural history 4. assess the long-term direct and indirect benefits and limitations of antiretroviral therapy on adults and children. We will continue to develop the capacity of the site as a centre of excellence for research and training, relevant to Malawi.
10,000 UK genome sequences: accessing the role of rare genetic variants in health and disease. 14 Dec 2009
We propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related m etabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. We will make the sequence data we obtain available for further research purposes, empowering many additional research directions both on these samples and by imputation on further samples from the UK and beyond.
Our goal is to understand how natural genome variation in human, Plasmodium and Anopheles populations affects the epidemiology and biology of malaria, and to use this knowledge to develop more effective ways of controlling the disease. This requires a concerted effort by many research groups around the world. We propose to establish a resource centre that will support this community effort by: - developing genome technologies and statistical methodologies to underpin global efforts to inv estigate genome variation in human, Plasmodium and Anopheles populations - building informatics systems and open-source web software for integrating and sharing large genetic and epidemiological datasets, to enable malaria researchers around the world to collaborate effectively to investigate how genome variation affects patterns of disease and biological phenotypes - providing scientific leadership in trans-ethnic genome-wide association studies of human resistance to malaria, and in de veloping a global system for monitoring Plasmodium populations by next-generation sequencing.
Clinical responses to anticancer therapeutics are often restricted to a subset of cases. Accumulating evidence indicates that response often correlates with a specific tumour genotype. Therefore, response rates could be substantially improved by directing treatment towards genetically-defined subsets of patients most likely to benefit. Toward this goal, we propose a scientific strategic alliance between investigators at Massachusetts General Hospital (MGH) and the Wellcome Trust Sanger Institute (WTSI) to "personalise" cancer therapy by identifying in vitro, prior to clinical trial, tumour cell genotypes that predict sensitivity to anticancer agents. We aim to expose approximately 1,000 cell lines derived from a broad spectrum of cancer classes to several hundred known and potential anticancer therapeutic agents correlating responses with genomic copy number information, cancer gene mutation data and expression data. Correlations between genotype or expression and response will then be validated in clinical specimens and will subsequently inform the design of clinical studies in which patients are stratified on the basis of a tumour genotype prior to treatment. The collaboration will develop and share the experience in automated high throughput exposure of cancer cell lines to small molecules at MGH and the background in large scale genotyping, sequencing and informatics at WTSI.
A Powerful, Genome-Wide Association Scan for Susceptibility Genes for late-onset Alzheimer's disease. 19 Sep 2007
This project aims to identify novel susceptibility genes for late-onset AD (LOAD) using high-throughput genome-wide approaches investigating over 500,000 variants, to test for genetic association, in a powerful sample of approximately 10,000 well characterised, LOAD cases and controls, which comprises the largest genetic association study currently undertaken. The study is timely and economical, exploiting samples collected through other funding, reducing genotyping costs without adversely affecting power through a staged design and bringing together genuine expertise in genotyping, clinical assessment and statistical analysis in the UK. First, we will select 1000 LOAD cases and 1000 matched controls from the MRC Genetic Resource and genotype on the Illumina platform using the HumanHap550 Beadchip. 30,000 SNPs showing evidence of association will be selected for further study in independent case-control samples comprising 1964 LOAD cases and 942 controls, from the Alzheimer's Research Trust (ART) and the MRC LOAD samples. A customised SNP Chip will be constructed of the selected SNPs and the samples genotyped on the Illumina platform. Finally, a meta-analysis of selected SNP's will be undertaken and the genes/variants which show the strongest evidence for conferring susceptibility for LOAD will be further genotyped in 4976 association based samples provided by US collaborators.
To support the development of the WASSUP project.
Volunteer Britain 14 Jul 2005
Community Service Volunteers (CSV) works to reconnect people to their community through volunteering and training and to enrich people?s lives. This project will produce short audio and visual clips on volunteer's experiences, produced by the volunteers themselves. CSV will showcase the clips in order to recognise their efforts and promote volunteering to others, through radio, TV and at local community events. This will be done in conjunction with the 'Year of the Volunteer' campaign.