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Results

Investigation of epithelial differentiation in a mouse wound model 31 May 2018

Lipoxygenase (LOX) enzymes are expressed by infiltrating immune cells and are involved in innate immune and inflammatory response, all of which are fundamental processes in wound healing. The overarching aims of this larger body of work is to evaluate the role of 12/15-LOX in the cellular orchestration of wound healing using a murine model. We have induced full thickness (4mm) wounds in wildtype and 12/15-LOX knockout mice, then measured wound closure rates and harvested skin tissue at various time points post wounding and conducted histological evaluation of skin sections. Our initial data has found that in 12/15-LOX knockout skin there is enhanced fibroblast expansion, and a reduced infiltration of macrophages, both of which might be beneficial in chronic wound states where failure in fibroblast proliferation and an overt inflammatory state occur. However chronic wounds also displays deficits in wound re-epithelialisation and given that 12/15-LOX products can inhibit epidermal hyperplasia (by modulating cyclin/CDK signalling), we believe that KO mice might also display an enhanced re-epithelialisation phenotype. Therefore, to test this hypothesis we will explore the rate of re-epithelialisation and the cytokeratin profile of epithelial keratinocytes in KO and wildtype mice at various time points post wounding.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Open Access Awards 2017/18 30 Sep 2018

Not available

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

How curiosity enhances hippocampus-dependent memory 06 Jun 2018

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

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

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

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

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

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

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

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

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £14,001
Funder: The Wellcome Trust
Recipient: University College Dublin

Prisoners, Medical Care and Entitlement to Health in England and Ireland, 1850-2000. 27 Jan 2014

Our project investigates health risks, medical interventions and health care in English and Irish prisons between 1850 and 2000. The two systems were interconnected in terms of administrative development and the high number of Irish prisoners in English prisons, yet varied in terms of the size of their respective populations, the impact of religious bodies on reform and in the role of political prisoners in shaping health. The largest research strand explores the high incidence of mental illness amongst prisoners and the impact of the prison system on the mental health of inmates, adults and juveniles, key issues which have preoccupied prison medical services and reformers from the early nineteenth century to the current day. Further strands examine the management of medical care and disease; responses to HIV/AIDS in prisons; the impact of political prisoners on medical regimes and prisoners' rights; the health of women prisoners; and the campaigns of lay and religious reformers in see king to improve facilities. The project interrogates inherent tensions as medical staff grappled to maintain healthy and hygienic practices, while devising regimens to discipline and rehabilitate prisoners in the context of poor conditions, official disinterest and intermittent overcrowding. Our case studies also consider the categories of gender, sexuality, class, age, religion, race, migration and ethnicity and how these influenced medical interventions. Alongside the production of scholarly o utputs, and a wide range of public engagement activities, our project will address current policy debates on prison systems, medical ethics and the management of prisoners' health.

Amount: £500,022
Funder: The Wellcome Trust
Recipient: University College Dublin

Defining mycobacterial host-pathogen interactions: the role of the secreted protein MPB70 31 Jan 2017

Tuberculosis is an infectious disease which in humans is caused by Mycobacterium tuberculosis and in cattle by Mycobacterium bovis. The genome sequences of these two bacterial species are 99.95% identical, with deletion of genetic information leading to a reduced genome size in M. bovis and no unique genes per se in M. bovis compared to M. tuberculosis. The high degree of genetic identity contrasts with the distinct host preference of the pathogens, and suggests that host preference is likely driven by differences in the expression of key genes between M. tuberculosis and M. bovis. We are particularly interested in two genes coding for secreted proteins, MPB70 and MPB83, which show significant differential regulation between the two species. Through combined in vitro infection assays with bacterial mutants, proteomics studies and in silico evolution studies of these genes and their regulon, we will investigate if MPB70 and MPB83 play a specific role in the host-pathogen interaction and the nature of this interaction. By elucidating the role of these proteins in host preference, we hope to increase our knowledge of host-pathogen interaction and to open new avenues for the development of disease control approaches in both human and bovine tuberculosis.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Genome evolution in the Candida clade 31 Jan 2017

The CUG-Serine clade, a group of yeasts including the common human pathogen Candida albicans, has been known to translate the codon CUG as serine instead of leucine for over 20 years. Recently, a sister species that translates CUG as alanine was discovered. In my bioinformatics rotation I discovered a second, independent CUG-Ser clade as well as a CUG-Ala clade and three separate CUG-Leu clades.In my PhD project I will examine tRNA gene evolution in these clades and test the hypothesis that they descended from a catastrophic event in their common ancestor in which the CUG- decoding tRNA was lost. I will perform experiments to artificially push a yeast species to change its CUG translation from Ser to Leu by replacing a tRNA gene, and monitor the effect on the proteome. In parallel, I will study centromere evolution in yeasts, which show an extraordinary diversity of centromere types, by using ChiP-seq to find centromeres across the Candida clade and beyond. This project will develop valuable new tools for manipulating Candida genomes, including transformation vectors that completely lack CUG codons and should work in any species, and potentially also new centromere-based plasmids for use in C. albicans.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Streptococcus gallolyticus gallolyticus pathogenicity 31 Jan 2017

Streptococcus gallolyticus is a gram positive gut commensal that can cause Infective endocarditis (IE) a heart valve infection. Unusually, in the case of S. gallolyticus, patients presenting with infective endocarditis are also found to have colonic abnormalities i.e. colorectal cancer. It is thought that the presence of colorectal cancer allows translocation of the pathogen from the gut lumen into the bloodstream. To date, there is limited information on the virulence factors of S. gallolyticus that contribute to the pathogenesis of IE. This study aims to (1) identify common virulence factors in clinical isolates of S. gallolyticus from bloodstream infections and IE. This will be achieved by sequencing and de novo assembly of the genomes of 50 clinical isolates from Ireland, France, Italy, Spain and the US. The relatedness of these strains will be analysed and virulence factors identified. (2) Genes encoding these virulence factors will be deleted and the ability of the mutant strains to adhere to platelets, trigger platelet aggregation and adhere to colonic epithelial cells will be tested. (3) These genes will also be cloned into expression vectors and expressed in a surrogate expression host to analyse any gain of function conferred.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

The role of innate immune regulation in viral pathogenesis and the development of anti-viral T cell memory 11 Jul 2017

Immune mechanisms that regulate antiviral immune responses determine whether the host can control pathogen replication and virus-induced immunopathology. The pathogenic human cytomegalovirus (HCMV) establishes chronicity and induces inflammation-associated pathologies. Cytomegalovirus (CMV) also induces the largest known expansion of T cells, and thus represents an important tool for identifying mechanisms inducing robust T cell immunity. CMV may also be exploited as an attenuated vaccine vector. Using a CMV model of viral pathogenesis, I identified that immune regulation during initial infection determines the extent of virus-induced inflammation and development of long-lived virus-specific immunity. The key goals of this proposal are: Identify innate immune components that mediate viral pathogenesis and understand how they are controlled Test whether innate immune pathways can be a) safely targeted therapeutically to treat viral disease and/or b) used to predict genetic risk of CMV pathogenesis Identify the early immunological events that promote CMV-specific T cell memory development, and elucidate whether regulatory pathways controlling these factors can be harnessed to enhance virus-driven memory T cell formation induced by attenuated viral vectors This research will determine whether innate immune activation can be exploited to: 1) safely treat viral pathogenesis and/or 2) enhance virus-induced T cell memory responses.

Amount: £1,942,612
Funder: The Wellcome Trust
Recipient: Cardiff University

Establishing objective measures for identifying children with Autism Spectrum Disorders using eye-tracking technology in the UK and India 09 Nov 2016

Autism Spectrum Disorders (ASD) contribute significantly to total years lived with disability globally. Most people with ASD in low-income countries are belatedly or never diagnosed, mainly due to the paucity of mental health specialists - hence critical years for treatment are missed. Objective measures for ASD detection are needed. Multiple cognitive markers of ASD have been identified using eye-tracking technology; testing these markers in combination holds promise for effective identification of children with ASD. This proposal aims to establish objective measures for identifying children with ASD using eye-tracking technology in high and low-income settings. Stage 1 will analyse existing eye-tracking data from the British Autism Study of Infant Siblings, to establish a combination of eye-tracking tasks that has the highest probability of identifying children with an ASD diagnosis. Stage 2 will be a case control pilot study to determine whether the same combination of markers identifies children with an ASD diagnosis in India. The feasibility and acceptability of these eye-tracking tasks will also be assessed in an Indian context. Establishing effective, acceptable and feasible methods for objectively identifying children with ASD will improve detection in these settings and translate into a greater number of children benefiting from early interventions worldwide.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

An investigation of the molecular mechanism of invasion of human epithelial cells by Campylobacter jejuni using a novel in vitro model based on altering bacterial DNA topology 27 Apr 2017

Campylobacter jejuni is the leading cause of bacterial gastroenteritis in the world. The organism is endemic in chickens where it appears to act as a commensal and is found in high numbers as part of the mucosal microbiome. In contrast the organism is highly pathogenic in humans where it displays an invasive phenotype which results in severe gastroenteritis and damage to the epithelium. The mechanism by which this important human pathogen invades the human epithelium is relatively poorly understood compared to other invasive pathogens primarily down to the fact that the organism invades at a relatively low frequency in vitro. Some studies have suggested the involvement of host cytoskeleton rearrangement whereas others have contradicted these findings. The Ó Cróinín laboratory have recently published data showing that invasion is induced by relaxation of DNA supercoiling using sub-inhibitory concentrations of novobiocin and that this results in a dramatic increase in invasion. The aim of this project is to use this induction of the invasive phenotype to study the interaction of C. jejuni with human epithelial cells in vitro and in particular to study the involvement of actin, tubulin and other host cell cytoskeleton molecules in this process.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Integrative Neuroscience. 14 Jul 2014

Not available

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University

Medicine and the Bishop in Medieval England, c.1100-c.1400. 04 Dec 2013

This project investigates the role of medicine in the life of the late medieval bishop, through an examination of three key themes. The bishop as a beneficiary of medical knowledge and treatment considers both medical provision within the episcopal household, and the role of preventative medicine (especially the six non-naturals) in protecting the bishop's health. The bishop's medical knowledge examines the medical knowledge of the late medieval episcopate: what medical knowledge did the bishop did, where did he obtain it from, and how did he use it? Understanding the bishop's body explores the role of medical knowledge in the formation of episcopal reputations, suggesting that medical interpretations of the episcopal body could be crucial in the formation of a reputation for sanctity or failure. Overall, the project aims to combine medical and ecclesiastical history in order to provide a detailed case study of the impact of medicine on a particular social group, and thus to improve ou r understanding of the links and potential tensions between spiritual and medical understandings of health and well-being as they existed in late medieval England.

Amount: £150,282
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Control of homeostasis and inflammation by the macrophage metabolome. 07 Apr 2014

Macrophages are a heterogeneous population of immune sentinels who shape the physiology of most tissues; this fundamental role often contributes to the pathogenesis of inflammatory disorders such as rheumatoid arthritis and cancer. Recently, marked heterogeneity in tissue-resident macrophage origins has been observed, with many having prenatal rather than adult bone marrow origins. Little is currently known about how the functions of these distinct macrophage populations are controlled. However, I have observed that the phenotype of tissue-resident macrophages can be directed through tissue-specific transcription factors, which control modulators of macrophage function including metabolic regulators. I have identified extensive regulation of metabolic enzymes during an inflammatory response with a clear disparity between bone marrow-derived and tissue-resident macrophages. These enzymes have the potential to direct distinct macrophage functions through both control of the metabolome an d direct interactions with key transcription factors. I hypothesise that precise regulation of metabolic enzymes is critical for specific macrophage function. The objectives are: i) characterise the metabolomes of distinct macrophage subsets during inflammation; ii) determine functional consequences of metabolic modulation; and iii) investigate specific functions of select metabolic regulators in inflammation in-vivo. Understanding how metabolic regulation controls cell function could lead to no vel therapeutic approaches to inflammatory diseases.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Medical training, student experience and the transmission of knowledge, c.1800-2014. 15 Sep 2014

Financial support is requested to assist the organisation of a two-day international symposium entitled 'Medical training, student experience and the transmission of knowledge, c.1800-2014' at the Humanities Institute, University College Dublin on 17-18 October, 2014. The main aim of this conference is to examine the theme of medical training and education, broadly conceived. There has not been a conference on the history of medical education since 1992, and this conference will represent the mo st cutting-edge research in the history of medical education in a variety of contexts and international settings. Considering recent concerns over standards of medical education the conference is timely. Moreover, there has never been an interdisciplinary conference on this theme. This conference will bring together not only historians of medicine, but also researchers working in related fields in the humanities, social sciences and medicine. It will allow for in-depth discussion in a relaxed bu t structured environment, with speakers being drawn from American, French, Irish, and British universities. Funding has already been attained from the Irish Research Council to cover accommodation expenses for speakers and conference catering costs. Funding is requested from the Wellcome Trust to contribute towards the travel expenses of the speakers.

Amount: £2,687
Funder: The Wellcome Trust
Recipient: University College Dublin

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £4,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London