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Results

Anopheles-Plasmodium interactions: mosquito immune response and parasite immune evasion strategies. 07 Jul 2015

Malaria parasites entering the mosquito midgut are eliminated by robust mosquito immune reactions, and only few remain to continue the transmission cycle. My principal research questions are: how mosquito immune reactions are activated on parasites and how some parasites evade these reactions. By answering these questions, I aim to gain fundamental understanding of the Anopheles-Plasmodium interactions leading to disease transmission. This knowledge could aid future translational research for th e development of malaria transmission-blocking interventions, contributing to the global effort for malaria elimination.

Amount: £20,930
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity 22 Feb 2017

Intestinal infections affect billions of people worldwide, resulting in nearly 1.4 million deaths each year. The commensal microbiota can prevent pathogenic infection, as demonstrated by increased susceptibility to infection upon antibiotic use; however, the precise mechanisms of microbiota-mediated protection are not well-characterized. I have recently discovered that colonization of mice with commensal Enterococcus faecium leads to improved intestinal barrier function and decreased Salmonella and Clostridium difficile pathogenesis. I went on to uncover a mechanism by which a unique enzyme, SagA, from these bacteria activates intestinal epithelial cells (IECs) to increase anti-microbial peptide (AMP) expression and mucin distribution. These studies revealed several host and microbiota factors involved in pathogen tolerance. My proposed independent research will identify the mechanisms by which commensal bacteria modulate IECs and intestinal immunity. Utilizing advance microscopy, proteomics and sequencing approaches, I will characterize the effects of E. faecium, SagA and other microbiota metabolites on IEC gene expression and function and subsequent pathogen resistance. Using proteomics-based bioorthogonal reporters and intersectional genetics, I will then dissect how microbial modulation of IECs affects the differentiation and function of intraepithelial lymphocytes. Elucidating the IEC programs triggered by commensal bacteria will enable better strategies to prevent and treat intestinal infections.

Amount: £13,200
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Immunogenetics of KIR and HLA-C variants in Ugandan women with disorders of pregnancy. 11 Aug 2014

We have shown that specific combinations of maternal and fetal immune genes predispose to reproductive failure. We will now identify the specific alleles that predispose to reproductive failure in humans. We will correlate, for the first time, maternal and fetal immune genotypes of large cohorts of normal and abnormal human pregnancies with blood flow dynamics at the experimentally inaccessible human maternal fetal-interface. Informed by these human genetic data we have designed experiments in mice to determine the downstream consequences of the interactions between maternal NK cell receptors (NKR) genes and fetal Major Histocompatibility Complex (MHC) genes on reproductive success. We will investigate in vivo exactly how these interactions control the mechanisms of vascular remodelling, placental development and fetal growth. A combination of cellular assays and transcriptome analysis will reveal the pathways activated in both maternal NK cells and fetal trophoblast cells upon int eractions with one another in both species. Bringing together human and mouse genetics, quantitative in vivo and in vitro assays and uterine

Amount: £20,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Mechanistic role of CUX1 in haematopoiesis and leukaemogenesis and identification of therapeutic vulnerabilities in CUX1-deficient malignancies. 13 Nov 2014

Complete or partial monoallelic losses of chromosome 7 [-7/del(7q)] are recurrent lesions observed in myelodysplasia (MDS) and acute myeloid leukaemia (AML), suggesting that chromosome 7q harbours tumour suppressors that promote disease development. Although these gene targets have been elusive, we recently identified inactivating mutations in the chromosome 7q transcription factor gene, CUX1, in MDS and AML cases, thereby implicating CUX1 as a key target gene lost in -7/del(7q) MDS and AML. In support, CUX1 mutations were found to confer adverse survival similar to the poor prognosis of -7/del(7q) MDS and AML cases. This proposal firstly aims to elucidate the function of CUX1 in haematopoiesis and leukaemogenesis in vivo by using a novel conditional Cux1 knockout mouse model we have generated. Secondly, by using genome-editing and transposon-mediated expression systems to generate epitope-tagged cell lines, this proposal aims to identify CUX1 target genes and interacting proteins that are critical mediators of CUX1 function. Finally, CUX1-deficient cells will be subjected to large-scale drug-sensitivity and genome-wide genetic synthetic lethality screens to identify drugs and genetic pathways that specifically target CUX1-deficient tumours. These complementary approaches will enhance our understanding of the role of CUX1 in cancer and identify potential new treatments for these poor-prognosis disorders.

Amount: £704,856
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Unravelling the networks that determine and control norovirus infection and pathogenesis. 26 Mar 2012

We aim to understand the mechanistic basis for why GII.4 noroviruses have dominated for the past 15 years as well as identifying new mechanisms of controlling and preventing norovirus infection. One goal of the project will determine the contribution of the viral RNA polymerase fidelity and activity to norovirus pathogenesis as the enzyme from pandemic noroviruses is more error prone and has higher activity than non-pandemic noroviruses. We will usecutting edge sequencing methods to characteris e norovirus evolution in the human population, identifying possible pandemic signature mutations in the viral RNA polymerase. We will then characterise the effects of these mutationson RNA polymerase activity, virus replication and virus pathogenesis, identifying new vaccine strategies. State of the art quantitative proteomics will be used to determine the effect of the norovirus replication on the host cell and the role of these pathways examined in more detail. We will then identify small mol ecule inhibitors of these pathways and examine if they haveanti-norovirus activity. We will also consider the role of the host cell RNA quality control pathway in the norovirus life cycle as our preliminary data indicates that this pathway provides an attractive therapeutic target.

Amount: £14,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

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.

Amount: £21,091
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

UK human iPS cell consortium: genotype to phenotype. 17 Apr 2012

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.

Amount: £143,750
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Sanger Costs for Annette MacLeod's SBBF (095201/Z/10/Z) - Genetic determinants of host/parasite interactions in African trypanosomiasis. 13 Apr 2011

The aim of this project is to examine the role of natural genetic variation in both the human host and parasite in determining the outcome of infection with either T.b. gambiense or T.b. rhodesiense. There is now a body of data, which shows there is variation in the factors that: (a) prevent initial host infection; and (b) determine disease severity. However, we have a relatively limited knowledge of the mechanisms involved and how genetic variation affects disease outcome. This proposal will ex ploit natural genetic variation to identify the key features and molecules involved using a combination of host association of candidate genes, parasite population genomics and molecular analysis of trypanolytic complexes present in serum. In addition, the proposal will create a large genomic sequence resource of >140 parasite strains together with a biobank of the parasites strains for those working in other areas. Thus, by dissecting some of the key components of both host and parasite which are determinants of infection and disease outcome, a series of pathways and molecules will be identified which could be the targets of novel interventions aimed at preventing or controlling the disease.

Amount: £118,679
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

CpG as a genomic signalling module. 22 Apr 2010

The self-complementary dinucleotide sequence 5 CpG3 occurs in the genome in three forms: unmethylated, methylated and, as demonstrated recently, hydroxymethylated. Our over-arching model is that this short sequence, despite its simplicity, is a genomic signalling module whose variable density and diverse modification status directly influence chromatin structures. This programme will test aspects of the model using biochemical, cell biological and genetic approaches. Our emphasis will be on com mon features shared by CpG islands and on proteins that potentially read the CpG signal by preferentially binding to either its non-methylated or its methylated form.

Amount: £75,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

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.

Amount: £920,144
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Combinatorial therapeutics to target the cancer genome 10 Oct 2013

Alterations in cancer genomes strongly influence clinical responses to anti-cancer therapies and can provide potent biomarkers to identify patients most likely to benefit from treatment. Despite some notable successes, such asBRAF mutations in melanoma, and EGFR and EML4-ALK mutations in lung cancer, the majority of cancers have not been linked to a genetically matched therapeutic strategy and most drugs do not currently have associated biomarkers to direct their clinical use. New genetic targe ts and novel drug classes hold great promise, but emerging data indicate that combinations of drugs will be necessary to obtain better and durable responses. The high ordercomplexity of drug combinations, many of which are unpredictable and tissue- and genotype-specific, necessitates methodical and high throughput preclinicaltesting as all potential combinations cannot be explored in clinical trials. Our proposed research aims at providing a framework for the discovery of novelcancer thera peutics and their clinical application. Our key goals are: 1. To discover therapeutic strategies combining targeted agents so as to circumvent native or acquired drug resistance. 2. To identify and validate clinical biomarkers of drug susceptibility across a spectrum of novel compounds. 3. Useclinically-derived cells to accelerate translation of our findings into early phase clinical trials.

Amount: £2,999,973
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

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.

Amount: £60,000
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Deciphering the Mechanisms of Developmental Disorders (DMDD). 12 Oct 2012

The proposal aims to capitalize on the unique resource of knockout mouse strains being generated by the Sanger Institute Mouse Genetics Project pipeline. Over the next 5 years the MGP primary screen will identify in excess of 250 genes essential for normal development. The DMDD project will employ high throughput imaging ( CT and HREM) of mutant embryos to identify and catalog structural developmental defects. Possible contributions resulting from disturbed placental development will be assess ed. Phenotypic characterization in conjunction with high-throughput transcriptomic analysis at defined developmental stages will provide new information about gene regulatory networks underpinning normal development. The efforts of the DMDD project will be guided by interactions with Deciphering Developmental Disorders and the MRC Developmental Anomalies Consortia, to prioritize generation and analysis of mutants in mouse genes orthologous to disease alleles identified by human genetic studies. The major output of DMDD will be a single, publicly-available database, fully linked into the International Mouse Phenotyping Consortium and designed to facilitate access by the clinical and developmental biology community. Our goals are dissemination of primary phenotyping information, encouraging maximal uptake of mutant strains by laboratories for future in-depth analysis and advancing identification of developmental disease alleles.

Amount: £2,683,074
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Mutational signatures of DNA damage and repair processes. 17 Apr 2013

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.

Amount: £3,295,091
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

WTCCC2 core activities. 12 Jan 2008

Not available

Amount: £7,758,317
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Non-var-Encoded Variant Antigen Families in Plasmodium falciparum as Targets for Naturally Acquired Immunity to malaria. 15 Jul 2008

The Plasmodium falciparum genome contains large multigene families that code for hypervariable antigens, which are exported to the surface of the infected host erythrocyte and represent targets of naturally acquired immunity to malaria. These variant surface antigens (VSA) act at the host-parasite interface, ensuring parasite survival without inducing a sterilizing host immune response. With the exception of the well-demonstrated roles of var-encoded P. falciparum erythrocyte membrane protein (PfEMP)1 in virulence and immune evasion, the biological significance of other VSA and their role in the acquisition of antimalarial immunity in endemic regions is largely unknown. Here we propose to determine whether two other VSA, RIFINs and STEVORs, encoded by the rif and stevor multigene families respectively, are targets of natural immunity and whether the hypervariable regions of these structurally-related proteins are exposed to antibody-mediated immune selection at the erythrocyte surface. We will define the expression patterns and measure the naturally acquired antibody responses to these antigens in wild isolates of P. falciparum from coastal Kenya. By identifying and characterising the molecular targets of naturally acquired immunity, this research will advance current understandings of P. falciparum antigenic variation and the mechanisms of natural acquisition of protective immunity against malaria.

Amount: £38,812
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

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.

Amount: £1,001,133
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

The Genomics of host adaptation in campylobacter 23 Jun 2009

A comparative functional genomics approach will describe the genetic basis and ecology of host specificity and niche adaptation in Campylobacter and how this relates to the emergence of virulence. Recent advances in Illumina GA resequencing technologies, specifically isolate multiplexing, enable high-throughput sequencing of multiple genomes and open the new field of population genomics . Large in-house isolate collections, genotyped at 7 loci, are the starting point for this multidisciplin ary fellowship studying the evolution and ecology of pathogens, in three major types of experiment: (i) Genome-wide association mapping in natural populations; (ii) Quantifying adaptability and generalism in in vitro experimental evolution systems; (iii) in vivo competition experiments in specific-pathogen free chickens. Genomic experiments will describe the mechanisms and nature of adaptations to host. The competition experiments will assay the absolute fitness differences of strains with diffe rent degrees of host-adaptation and allow rigorous tests of specific adaptive hypotheses. The laboratory experiments will help to elucidate variation in genome plasticity and its relationship to host adaptation. Experimental results will feed into the Genome Evolution by Recombination and Mutation (GERM) program, designed for this project to provide a systems approach to the investigation of niche adaptation and population structuring in bacteria.

Amount: £28,335
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute

Quantifying disease burden in patients with cancer using tumour-specific genomic rearrangements 26 Feb 2010

Cancer is caused by the accumulation of genetic damage (mutations) in cells within a particular organ. These mutations are only found in the cancerous cells and therefore could be used to track the malignancy during treatment. Advances in DNA sequencing allow the high-throughput identification of these mutations from any cancer sample in a clinically relevant time-frame. As tumour cells die, they release their DNA into the bloodstream. Dr Peter Campbell, Wellcome Trust Sanger Institute and colleagues propose to use the new generation of genetic sequencing technologies to identify a particular class of mutations caused by the abnormal rearrangement of chromosomes in patients with breast cancer and colorectal cancer.From these rearrangements, the team will develop assays to detect DNA from each patient's cancer that has been released into the bloodstream. Such assays will be highly specific (minimal risk of falsely positive results) and sensitive (capable of detecting one copy of tumour DNA in many millilitres of blood). The programme will measure the amount of disease using blood samples collected before surgery, after surgery, during chemotherapy and at regular time-points post-therapy. Dr Campbell and colleagues will therefore be able to assess the ability of this approach to identify high-risk patients before treatment begins, to monitor response to treatment and to predict cancer relapse before it is clinically apparent.

Amount: £840,844
Funder: The Wellcome Trust
Recipient: Wellcome Trust Sanger Institute