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Results

EVIPNet Europe policy and research scoping tool 18 Jun 2018

I propose to develop a policy and research prioritisation tool for use by EVIPNet Europe countries to improve knowledge translation between research and policy. The goal would be to create a ranking system to help health policy decision-makers pinpoint high-priority policy issues that would benefit from research input in clarifying the problem or framing options for its solution. It should also aid research policy decision-makers to identify where to invest research resources, taking into account policy needs, to create implementable recommendations. Such a tool would encourage decision-makers to analyse quantitative data, for example the burden of disease, and qualitative information, such as public attitudes, and reach agreement when allocating resources to programmes. To create it I would complete a scoping literature review on the merits of various existing tools and combinations of tools. I would gather a variety of evidence, including systematic reviews of best practice, and case studies from the region that explain how these tools have been adapted to work in similar settings. I would consult with the EVIPNet country knowledge translation networks on their particular research and policy needs and challenges so as to select and adapt a context appropriate design for the tool.

Amount: £14,388
Funder: The Wellcome Trust
Recipient: University of York

Using examination questions to assess practical skills in science 26 Jun 2017

The principal aim of the project is to identify the features of written examination questions that discriminate between students who have had substantial hands-on experience of practical work in GCSE science and those who have not. This project is important because recent changes in assessment mean practical skills are now wholly assessed through written examination questions. It is therefore essential to have a valid means of assessing practical skills that rewards students who have undertaken hands-on practical work. A series of classroom interventions will be developed in which students experience a practical activity either as hands-on practical work, a teacher demonstration, a video recording, or through a written description. Students will then complete written examination questions relating to the interventions. The outcomes will be: examples of questions that discriminate between students with different levels of hands-on practical experience, together with insights into characteristic, generalisable features of such questions guidance for examiners to support them in question writing evidence of the validity of the use of written questions to assess practical skills with a view to informing future iterations of the science curriculum. The project Advisory Group comprises representatives of the Awarding Organisations, Ofqual, the learned societies, ASE and science teachers.

Amount: £210,838
Funder: The Wellcome Trust
Recipient: University of York

Expanding the capabilities and use of the South West Regional Facility for High-Resolution Electron Cryo-microscopy 07 Dec 2016

State-of-the-art direct electron detectors (DEDs) and new image processing strategies enable electron cryo-microscopy (cryoEM) routinely to achieve near-atomic resolution of biological samples. CryoEM has thus become a primary imaging technique, increasing the need for research institutions to provide cutting-edge cryoEM equipment. The Living Systems Institute (LSI) at the University of Exeter is a brand new interdisciplinary research centre, which will develop strategies to study diseases and their prevention. As part of the GW4 group (also including Bristol, Bath and Cardiff), we seek to develop regional research infrastructure on a scale beyond the capabilities of the single institutions. Within this remit, the Wellcome Trust-funded South West Regional Facility for High-Resolution Electron Cryo-microscopy will be established in Bristol, with a 200kV cutting-edge cryo electron microscope at its core. To support this venture and significantly increase the capabilities of the facility for all users within GW4, we plan to contribute a state-of-the art K3 DED with energy-filter. We also plan to establish an entry-level multiuser cryoEM facility at the LSI, supporting the research needs of local users in order to provide samples for further high-resolution analysis in Bristol and at the Wellcome Trust-funded electron Bio-Imaging Centre (eBIC) at Diamond.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of Exeter

Re-Engineering Health Policy Research for Fairer Decisions and Better Health 01 Feb 2017

Health inequalities diminish lives and blight communities. Although the determinants of health inequality are well known, policy makers have repeatedly failed to address the issue effectively, and many public health interventions unwittingly worsen inequalities because they disproportionately benefit those with greater resources. This is also a scientific failure. The analytical tools used to inform policy lack a substantial perspective on equity, focusing on averages rather than social distributions, leading to inequitable solutions. In an age of social division driven by rising inequality, new approaches to health policy are urgently required. We propose to re-engineer health policy research. We will develop rigorous methods for measuring the equity impacts of health and social policy interventions, and apply these methods to assess the effectiveness of major public health and healthcare initiatives. In doing so, we will improve our understanding of the structural, behavioural and organizational barriers to delivering equitable health outcomes. Our programme will equip researchers with the necessary tools for measuring equity impacts, and provide policy makers with vital information on who gains and who loses from their decisions. Our ultimate aim is to enable fairer health policy decisions, leading to better health across society.

Amount: £872,588
Funder: The Wellcome Trust
Recipient: University of York

Regulation of immune checkpoint expression in human primary cells 31 May 2018

The host lab investigates post-transcriptional mechanisms that regulate expression of immune checkpoint membrane proteins in human primary dermal lymphatic endothelial cells (HDLECs) and dermal fibroblasts and recently demonstrated that PD-L1 is regulated by miR-155 (Yee et al., 2017, JBC). It has been suggested by others that resistance to therapeutic PD1 blockade is associated with alternative immune checkpoints in cancer cells, specifically the Gal9/TIM3 signalling axis. In this project, expression of Gal9 will be measured in unstimulated cells and cells treated with TNF and/or IFNg and upon over-expression or inhibition of miR-155. Experiments will be performed in both HDLECs and fibroblasts. Using already available small RNA sequencing data in the lab, miRNAs that can potentially suppress Gal9 expression and are significantly regulated upon treatment of HDLECs with TNF and IFNg will be identified. This will allow us to propose post-transcriptional regulatory networks that operate in non-transformed cells to control expression of a therapeutically relevant immune checkpoints. Training will include becoming familiar with cutting edge concepts in immunology and post-transcriptional gene silencing and techniques in primary cell culture and determining protein and mRNA expression, as well as extracting information from large transcriptomics datasets and using online in silico tools.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of York

The development of insulin resistance and anabolic resistance during muscle disuse: what is the role of fuel integration? 08 Nov 2017

Skeletal muscle atrophy, which occurs during short-term disuse, is thought to be due to the development of anabolic resistance of protein metabolism and insulin resistance of glucose metabolism, although their cause is currently unknown. The primary research aim of this fellowship is to establish the role of muscle fuel availability and integration in disuse-induced insulin and anabolic resistance. In collaboration with the Medical School, I will perform two randomized, placebo-controlled studies in which young, healthy participants undergo 2 days of forearm immobilisation with placebo, Acipimox (to decrease plasma lipid availability), Formoterol (to stimulate glycolytic flux), or dietary branched-chain amino acid (BCAA) manipulation, to alter substrate availability. I will combine the arteriovenous-venous forearm balance technique, that I have recently established in Exeter, with stable isotope amino acid infusion and repeated forearm muscle biopsies to quantify muscle glucose, fatty acid, and BCAA balance, oxidation, and intermediary metabolism (including muscle protein synthesis), both fasted and during a hyperinsulinaemic-euglycaemic-hyperaminoacidaemic clamp. Two periods of research at the University of Texas Medical Branch will enable me to develop skills in mass spectrometry tracer analyses and develop a network of collaborators in the USA, both crucial for my future career investigating disuse-induced muscle atrophy.

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

Neurobiological mechanisms of emotional relief in adolescents with a history of sexual abuse 06 Dec 2017

Adolescents who experienced childhood sexual abuse (CSA) engage in non-suicidal self-injury (NSSI) more frequently than peers exposed to other forms of abuse or no abuse. NSSI serves an important function of relief from acute negative affect. Despite providing temporary relief from distress, NSSI is also linked to higher rates of suicide and hospitalisations and the effectiveness of current clinical interventions is limited. This may be attributed to a lack of understanding the neurobiological and behavioural mechanisms that underlie NSSI as a relief function in particular in youth who experienced CSA. To address this gap, the study aims (1) to model brain activity during distress and emotional relief (i.e., NSSI) in adolescents with and without a history of CSA using functional magnetic resonance imaging and (2) to examine if adolescents with CSA select actions to 'escape' an aversive context more quickly and often compared to non-abused peers. The ultimate goal of this translational research is to understand the neurobiological and behavioural mechanisms that confer vulnerability to NSSI following CSA (Stage 1) in order to develop effective intervention and prevention strategies to keep vulnerable teenagers safe (Stage 2) . Keywords: sexual abuse, non-suicidal self-harm, relief, functional magnetic resonance imaging, translational research

Amount: £230,048
Funder: The Wellcome Trust
Recipient: University of Exeter

Digital Spatial Profiling in biomedical research 05 Jul 2018

The key aim of this application is to provide capacity for medium throughput targeted transcriptomic and protein expression analysis appropriate for, but not limited to, analysis of scarce and challenging clinical samples. Capital equipment costs are requested for the purchase of a Nanostring Digital Spatial Profiler (DSP) Instrument together with a nCounter Max Analysis System. The DSP will become available commercially in late 2018 and provides a unique approach to non-destructive multiplexed immunohistochemistry and gene expression profiling. Maintenance costs for a five-year period are also requested. To ensure effective, open access to this equipment for researchers across the region, salary support for a dedicated technician for a period of five years will be provided in kind by the University of York. This new 5 year post will be based in the Dept. of Biology’s Biosciences Technology Facility, a core facility with an international reputation for training and technology development in the area of imaging and cytometry. Continuation of this post beyond 5 years will be funded through new grant applications based on the use the instrumentation.

Amount: £449,360
Funder: The Wellcome Trust
Recipient: University of York

Santorio Santorio and the Emergence of Quantifying Procedures in Medicine at the End of the Renaissance: Problems, Context, Ideas. 12 Jan 2015

While mechanics and astronomy have always been placed at the heart of the major narrative of the scientific revolution, historians are currently reconsidering disciplines or ways of thinking once regarded as peripheral, in particular medical disciplines such as anatomy and physiology. In this context, a study on the Italian physician Santorio Santorio (1561-1636) could be particularly noteworthy. Santorio is reputed to be the first to conceive and apply the quantification of the so called 'persp iratio insensibilis' in his major work 'Ars de statica medicina' (Venice 1614). Although developed in the context of traditional medicine, concepts such as 'weight', 'measurement' and 'certainty' became essential pillars of his thought and for this reason, Santorio invented many scientific devices, among which were the first graded thermometers. Despite his relevance, however, there are no recent studies on Santorio. The goal of my research would be to illustrate the medical impetus towards cont rolled experimentation and quantitative measurement in the cultural context of the end of the Renaissance. Considering Santorio's wide legacy across the Europe, the research would also show how the development of instruments has driven medicine in the late seventeenth and early eighteenth centuries.

Amount: £127,884
Funder: The Wellcome Trust
Recipient: University of Exeter

Gender stereotypes in ADHD diagnosis. 31 Mar 2015

This small-scale social epidemiology project seeks to establish evidence for a gender bias in the diagnosis of childhood Attention Deficit Hyperactivity Disorder (ADHD). It will question whether boys are more likely to receive a diagnosis than girls, given equally severe symptoms. Social epidemiologists in child psychiatry have suggested there is likely to be both real differences in ADHD symptomology between genders and additional referral / identification bias towards boys. The latter m ay be because ADHD is stereotyped as a 'male disorder', therefore boys are more likely to be assigned the label, whereas girls with comparable difficulties are overlooked. The methodology will be a secondary analysis of data from a birth cohort which comprises 14,000 children. Two groups, one with, and one without ADHD diagnosis will be matched on symptom severity. Gender ratios will be compared between these two groups. It is important to establish whether there is referral/ labelling bia s to help clinicians recognise girls who might benefit from ADHD diagnosis. The findings will also inform on-going debates about over-diagnosis of ADHD in boys. Outputs include one journal article, a press release, and workshops with ADHD charities.

Amount: £4,985
Funder: The Wellcome Trust
Recipient: University of Exeter

Detinova on Safari: Forgotten Histories of Global Health. 27 Oct 2014

This pilot project explores the influences of Soviet tropical medicine in Sub-Saharan Africa. It takes as its focus a method of mosquito dissection pioneered in the 1940s by a team of vector biologists based at the Moscow Martsinovsky Institute. The Detinova Technique offered a way to determine the exact physiological age of the female mosquito and provided insight into the dynamics of disease transmission. Heralded as a game-changer for global malaria eradication efforts, the technique prompted new collaborations and rivalries between East and West. The global health trajectory of this method reveals alternative histories of malaria control through a rather different set of techno-scientific circulations than those commonly associated with the WHO. Extending previous ethnographic and archival research conducted in Africa with archival and memory work in Russia and the UK, this project explores the significance of this scientific exchange for our current understandings of malaria contr ol and the Cold War, advancing a rapprochement in Anglo-Russian histories of global health.

Amount: £4,977
Funder: The Wellcome Trust
Recipient: University of Exeter

MA History 30 Jul 2017

My project researches associations between fat bodies and gender in the medical literature of early modern Europe. While modern concerns with increasing rates of obesity are reflected by a growing historical scholarship on this topic, much remains to be examined, especially concerning the link between cultural ideas about fat bodies and the medical understandings of these bodies. The purpose of this research is to assess gendered ideas in early modern medical discussions on obesity. I will do so by examining European medical texts between 1650 and 1750, particularly comparing English medical debates with those occurring in the Netherlands in the same period. The goal of this comparison is to locate and explain differences in the extent to which gendered assumptions about obesity informed medical debates in each country, in different schools of thought, and even between individuals. I will assess the nature and causes of different explanations and treatments of obesity within the context of cultural, as well as medical developments, unique to period, place, and practitioner. I will demonstrate how and why gender played a role in the diagnosis and prescriptions for cures of obesity.

Amount: £22,440
Funder: The Wellcome Trust
Recipient: University of Exeter

Probing the role of outer membrane transport processes in host-­pathogen interactions using computational and single-­molecule biophysical approaches. 31 Jan 2017

The outer membrane (OM) of Gram-negative bacteria is a significant protective barrier. It is composed of an inner leaflet of phospholipids and an outer of lipopolysaccharide (LPS) with OM proteins (OMPs) that span the membrane. Recently OMPs have been shown to be inserted at discrete and non-uniform locations across the membrane, where they remain due to restricted lateral diffusion. These ‘islands’ are pushed to the poles by cell growth, with new material inserted at mid-cell. OM turnover during bacterial growth may have a role in immune system evasion. One key mechanism regulating human immune responses is the assembly of complement components on the OM nucleated by immunoglobulin binding. This process can lead to lysis of bacteria through insertion of pore complexes in the OM. Complex formation depends on localised clustering of antibodies, which is constrained by the location and molecular diffusion of antigens in the OM. In this project we will use computational and single-cell biophysical techniques to test our hypothesis that spatial confinement of LPS and OMPs near their insertion sites influences activation of the antibody-mediated complement pathway. We will test our hypothesis in Escherichia coli and Salmonella typhimurium, where immune evasion has a key role in pathogenesis.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of York

Characterising the composition of low temperature air plasma to assess applications for wound infection and healing 31 Jan 2017

Wound infections, coupled with increasing antibiotic resistance are a global issue, and low temperature plasma (LTP) presents an interesting alternative treatment strategy as it has been shown to be bactericidal and to promote wound healing. LTP is characterised by a low degree of ionisation, a non-thermodynamic equilibrium and a dry reactive environment. Here, we propose the development of a nano-/microsecond pulsed, kilohertz repetition frequency air plasma. The plasma will be characterised both experimentally and computationally, in terms of reactive oxygen and nitrogen species concentrations, optical emission and temperature. This is of interest when considering LTP as a low-cost wound treatment, as air plasma should not require expensive bottled gases, thus decreasing running costs and increasing transportability. In terms of biological interaction, the aim is to use the characterised plasma to correlate plasma composition with (1) the difference in tolerance to oxidative stress between bacterial and eukaryotic cells and (2) the effects of plasma on the dynamics of healing-related gene expression in epithelial cells post wounding. The project should offer new insights into the development and characterisation of air plasmas, and their potential for use in biomedical applications, in particular wound infection and healing.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of York
Amount: £63,702
Funder: The Wellcome Trust
Recipient: University of Exeter

The Rowntree Archives: Poverty, Philanthropy and the Birth of Social Science 18 May 2017

The project will arrange, describe, publicise and make publicly available the archives of the Rowntree Trusts and the Rowntree family for the first time. The outputs: open key 20th century archives on public health in the UK, including research about health problems caused by or related to alcohol, unemployment, housing, old age, and betting and gambling; open for research key records documenting the theory and practice of relationships between employers, philanthropy, social justice and public health; provide materials for researching the birth and early development of social science in the UK; will establish regular transfers of records from the Trusts to the Borthwick, thereby securing for public use records yet to be created. We will do this by creating fully searchable online finding aids to international standards, with authority files and access points mediated by current experts in the field, and links to related archives in York and elsewhere. The project’s success measures are: the production of publicly accessible online catalogues; the creation of research projects based on the archives; securing a sustainable future for the archives, including future archives.

Amount: £114,930
Funder: The Wellcome Trust
Recipient: University of York

Understanding Leishmania parasite populations in Brazil. 05 Sep 2017

Leishmaniasis is a globally distributed disease of poverty that infects 700,000 people annually. It is caused by Leishmania parasites, spread by sand flies. The most severe form, visceral leishmaniasis (VL), is generally fatal if untreated. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the disease burden. Leishmania infantum was introduced to Brazil from the old world, and is becoming more common with urbanization, with 6,000 cases of VL in Brazil each year. There are indications of resistance to miltefosine in Brazil, which is an effective drug in other continents. Key goals of this project are to establish an understanding of the dispersal and evolution of Leishmania infantum in Brazil, which will be critical aspects of disease control. To achieve this, we will sequence the genomes of 200 strains of this parasite that have collected from two locations in Brazil that are 1600 km apart, and includes strains archived 20 years ago. By examining the movement of alleles between sites and over time, we can measure migration rates, recombination rates and screen for adaptive evolution. We will also analyse clinical data to examine whether parasite genes influence disease severity.

Amount: £94,476
Funder: The Wellcome Trust
Recipient: University of York

University of Exeter Medical Humanities Postgraduate Conference. 27 May 2014

The Centre for Medical History at the University of Exeter will be holding a two day interdisciplinary medical humanities conference for postgraduate students on the 24th and 25th July 2014. The conference will bring together the highest quality postgraduate research in all fields of the medical humanities and encourage cross-disciplinary discussion. In addition to papers from forty delegates the event will also include two keynote addresses, a panel discussion with keynotes and department membe rs, and a presentation from Wellcome Trust representatives about humanities funding opportunities.

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University of Exeter

Science is for Parents Too - Extension. 16 Sep 2013

The project will promote adult engagement with biomedical sciences through a sustained learning programme for parents (with limited scientific education) of primary school children. As a result of this science enrichment initiative, parents will be better able to support their children's education and career options with regard to the sciences. Broadly aligned to the Key Stage 2 science curriculum, we will focus primarily on biomedical science, with elements of complementary chemistry, physics a nd maths through a biomedical lens to demonstrate the relationships between the sciences. Our proposition is that raising aspiration is best effected by cascading learning through the family, to ensure that education becomes recognised as a viable proposition for all within a household. The intention is to make an impact on both the adults who engage directly and their immediate family circle, in an attempt to make bioscience a topic for family conversation, encourage scientific questioning, and erode past negative experiences. The learning experience will be delivered in a creative and imaginative way, with practical demonstrations of concepts, complemented by science site visits and experiments which can be undertaken with the family. We perceive this as a pilot which will develop a sustainable teaching resource that could be deployed elsewhere. It will be delivered in partnership with the National Science Learning Centre which will host taught sessions; the possible longer-te rm ambition however is to upscale the project and deliver via the regional Science Learning Centres and NSLC partners in the devolved nations, to gain national coverage.

Amount: £29,560
Funder: The Wellcome Trust
Recipient: University of York

Systems Investigation of Germinal Centre Formation. 24 Jun 2013

Invading pathogens can rapidly infect tissues inducing pathology. The immune system has developed an efficient mechanism for creating large amounts of highly specificantibodies through B lymphocytes undergoing affinity maturation in the germinal centre. The spatial organisation of a germinal center is a key determinant of its efficacy. In order for B cells to achieve high levels of affinity and avidity they must shuttle betweentwo anatomically distinct areas under the influence of specific chemokine gradients. However, the key mechanisms leading to germinal centre formation and chemokine field induction are not well understood. This leads us to ask the following question: Given that germinal centres are heterogeneous structures, how do chemokine mediated signals affect their formation and subsequent spatial organisation; thus determining protective immunity? We propose to combine in silico multi-scale modelling with in vivo experimentation to address our research question and ultimately to gain a novel mechanistic understandingof a complex biological process.

Amount: £149,673
Funder: The Wellcome Trust
Recipient: University of York