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Results

The Promise of 'Wellness': Understanding Alternative Dietary Practices in Precarious Times 23 Jul 2018

From ‘green juice’ to ‘golden milk’, ‘energy balls’ to ‘spiralised squash’, ‘activated charcoal’ to ‘bullet-proof coffee’, a whole host of supposedly health-enhancing dietary practices have become popular in the UK under the auspices of ‘wellness’. While such trends generate significant media attention and are cause for concern among medical professionals, they remain poorly understood and frequently trivialised. This study will be the first to interrogate the social, economic, and political forces underwriting the rise of wellness culture in Britain and account for its distinctly gendered contours. Rather than debating what actually constitutes ‘healthy eating’, it will use the tools of social and cultural analysis to understand why scientifically unfounded dietary trends are flourishing. Ethnographic methods will explore the glamorous trappings and mundane entanglements wellness generates in women’s everyday lives, and investigate how health practitioners grapple with the proliferation of anti-expert nutritional guidance as manifest online and in clinic. The project represents an original investigation into the cultural mediation of health. Key goals include: - Understanding why women embark on alternative dietary regimes. - Situating the rise of wellness culture within the broader cultural politics of austerity. - Finding ways to enhance communication on issues of food and diet.

Amount: £183,125
Funder: The Wellcome Trust
Recipient: University of York

Developing tools for fission yeast quantitative genetics 31 May 2018

Complex traits play roles in various human diseases, with multiple genes being implicated, as identified by genome-wide association studies. The advent of genome-editing techniques such as CRISPR/Cas9 has ushered in the idea that these genes can be repaired to cure the disease, as shown for monogenic hereditary disorders. However, it is unclear whether these will be able to repair conditions influenced by multiple genetic factors, and the complexity of multicellular eukaryotes makes it difficult to predict the outcome. Herein, the fission yeast, Schizosaccharomyces pombe, could provide a useful tool, as its comparatively smaller genome and ability to breed strains facilitates studies of accurate quantitative genetics. However, this model requires improvements before it is suitable. The tendency for wild-type strains to self-mate causes difficulties when conducting inter-strain crosses. Therefore, we propose to engineer stable heterothallic strains to guarantee outbreeding using a counter-selectable Cre/loxP construct to remove the H1 box at the mat1 locus. We will then test to confirm that transformation has been successful and determine whether they are h+ or h-. This allows a simpler and more reliable approach to inter-strain mating, allowing for the production of larger library of genetically diverse strains for the analysis of complex traits.

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

Assessing human immune organ architecture in a humanised mouse model following schistosome egg injection 31 May 2018

This research will assess human immune organ architecture in humanised mice following injection with schistosome eggs. We will generate tissue samples from the spleen, lymph node and bone marrow from naive and schistosome-immunised mice to compare and contrast the localisation of CD4 T cells, B cells, macrophages, dendritic cells and eosinophils. We do not know much about whether these cells interact together in a way that produces a string type 2 immune response, this project aims to test this in an acute model of immunity.

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

Neuronal oscillations in disease 01 Apr 2016

Rett syndrome is a devastating neurological disorder affecting females and is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Affected girls develop normally during the first 6 to 18 months of life but quickly regress, losing acquired language and motor skills, and later develop seizures, cognitive deficits, and stereotyped hand movements. The development of Mecp2 mutant mouse models mimicking RTT symptoms have improved our understanding of the disorder. Despite this progress, the mechanisms though which loss of MeCP2 affects the brain at the cellular and neural network level are poorly understood. Recent work has demonstrated that loss of MeCP2 leads to alterations in hippocampal gamma oscillations. These neuronal oscillations (30-50 Hz) play important roles in sensory processing, and memory storage and retrieval and thus may contribute to the symptoms in Rett syndrome. Here, I propose to use genetic tools to determine whether the preservation of MeCP2 in GABAergic interneurons of otherwise Mecp2-null mice can rescue impaired hippocampal gamma oscillations. These findings will increase our understanding of the cellular mechanisms that contribute to behavioural manifestations in Rett syndrome.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of York

Public engagement provision 27 May 2014

Not available

Amount: £37,000
Funder: The Wellcome Trust
Recipient: University of York

The Nature of Religion, Science and Health. 31 Mar 2014

A major academic event that will discuss the links between religion, science and health, from medieval times to the present day. Built around keynote addresses presented by four leading historians of science, medicine and health, the event will also involve a panel of influential respondents drawn from academia and religion to debate the points made in the keynote addresses. The event, which will be organised at the Theatre Royal in York and/or the York Minster, will then involve a detailed roun d-table discussion, and general question and answer session. These discussions will be chaired by major public figures (the University is currently in discussion with Melvyn Bragg, Jeremy Paxman and Rowan Williams to join the programme). This two day event will also be made a part of the York Festival of Ideas so that a very serious public engagement activity gets included and to ensure that the audience is large.

Amount: £4,980
Funder: The Wellcome Trust
Recipient: University of York

Integrated multi-user crystallisation facility comprising a robot and storage system with image retrieval. 08 May 2013

The key objective of this proposal is to equip the Structural Biology Laboratory at York with a modern facility to allow exploitation of cutting-edge new technologies in protein crystallisation; the critical step in X-ray structure determination. The bid aims to create a new-generation facility that will enhance our ability to generate diffraction quality crystals. This will underpin York research into proteins of relevance to human health by: (i) enabling high-throughput protein crystallisation , (ii) facilitating expansion into membrane proteins and challenging eukaryotic systems, (iii) underpinning disease research initiatives between the Chemistry and Biology Departments thus ensuring YBSLs position as an international centre of excellence. This proposal requests partial funding for a crystallisation robot and for a crystallisation storage and imaging system. Our major objective is to advance research on proteins relevant to human health. In particular we highlight our work on: i) viral proteins involved in replication and virus assembly ii) structural and functional crosslinks between diabetes and cancers iii) carbohydrate processing enzymes and glycans in health and disease iv) proteins involved in biofilm formation on medical devices v) methodologies for structure and fragment-based drug discovery vi)molecular mechanisms of protozoan infection in the search for new therapeutic strategies

Amount: £474,817
Funder: The Wellcome Trust
Recipient: University of York

Investigation of Chlamydia trachomatis PmpD and OmcB proteins as candidate vaccine immunogens and adhesins using structural and in vivo 18 Dec 2012

Chlamydia trachomatis, an obligate intracellular bacterium, is the leading cause of preventable blindness worldwide, affecting between 300-500 million people, and is also the most common sexually transmitted disease with over 90 million new cases reported annually. Development of a vaccine has not been prioritized, probably due to the availability of antibiotics to treat the disease, difficulties in culture and genetic manipulation, and a limited understanding of the factors involved in host cell binding. The project aims to investigate two proteins as candidate vaccine immunogens, which are also implicated in chlamydial epithelial cell attachment - polymorphic membrane protein D (PmpD) and outer membrane complex B protein (OmcB). Initially, expression, purification and structure determination of the proteins will be carried out using X-ray crystallography to elucidate the nature of potential antigenic fragments. These in vitro and in silico approaches will be complemented by in vivo studies on C57BL/6 mice using identified recombinant PmpD and OmcB subunits as vaccine immunogens. Co-crystallisation experiments with PmpD and OmcB recombinant proteins and their putative ligands will be carried out to elucidate binding mechanisms that may facilitate the design of novel blocking agents and inhibitors.

Amount: £18,300
Funder: The Wellcome Trust
Recipient: University of York

Modelling RNA regulatory networks in infectious disease 18 Dec 2012

The strength and duration of the innate immune response is regulated at the post-transcriptional level by miRNAs. miR-132 has been previously shown to suppress the anti-viral response. Interestingly, a miR-132 predicted target is ARGONAUTE-2 (AGO2), a protein involved in miRNA biogenesis and function. These findings create an opportunity to investigate the interaction between miR-132 and AGO2 in the context of the innate immune response. We aim to study the effect of miR-132 on the functional activity of AGO2 in an experiment-and-modelling coupled approach by (a) measuring the abundance of relevant components of the miR- 132/AGO2 interaction system in vitro and ex vivo, and (b) building an agent-based model (ABM) of the interaction in the context of viral infection and the immune response.

Amount: £4,555
Funder: The Wellcome Trust
Recipient: University of York

Kinome-wide functional analysis of Leishmania growth and differentiation 05 Apr 2016

Leishmania species are trypanosomatid parasitic protozoa that are the causative agents of a spectrum of diseases, the leishmaniases. Whilst significant progress has been made in understanding the unique cell biology of Leishmania and its interaction with the mammalian host, little is known about the signalling pathways that regulate key events in the parasites’ life cycle and which protein kinases are essential and therefore potentially amenable to chemotherapeutic modulation. To address this we will carry out gain-of-function and loss-of-function genetic screens in Leishmania mexicana to identify protein kinases involved in signalling pathways regulating parasite differentiation during transition between animal and sandfly hosts. We will also identify those protein kinases essential for proliferation and survival of Leishmania once an infection is established in the two hosts. This will be possible because of recent development in genetic manipulation of Leishmania, including CRISPR-Cas9 genome engineering, tetracycline inducible over-expression and the use of rapamycin induced diCre recombinase to study the function of essential genes. The expected output of the project will be novel insights into protein kinase function in Leishmania and a holistic overview of cell signalling pathways that will integrate into ongoing "omics" analyses within the Leishmania community.

Amount: £1,711,568
Funder: The Wellcome Trust
Recipient: University of York

Investigating Flagellar Motility of Leishmania spp.; its Impact on Parasite Lifecycle Progression and Infectivity 30 Sep 2016

Leishmaniasis is a chronic, debilitating disease that is the second biggest killer amongst parasitic diseases. It is caused by the obligate, intracellular protozoan Leishmania spp. [1] which undergoes a complex life cycle transitioning between promastigote and amastigote stages in sandfly and human hosts, respectively[1]. The different lifecycle forms each have a different aim. Whether that aim is migration within the sandfly’s midgut or infection of leukocytes, each involves motility of the promastigote form to enable the lifecycle to progress. We will use a myriad of techniques to examine the role of parasite motility in Leishmania : host interactions – investigating movement parameters, fluid dynamics and evidence of chemotaxis to compare different promastigote lifecycle forms. We hypothesise that studying the biophysical swimming parameters and biomolecular factors may reveal good therapeutic targets to block Leishmania spp. transmission to human hosts and/or invasion of mammalian immune cells. With the aim of correlating motility at individual, population and genetic levels this could elucidate the Leishmania parasite’s mechanisms for survival and transmission to human hosts.

Amount: £7,324
Funder: The Wellcome Trust
Recipient: University of York

Connecting wounds: nonsuicidal self-injury in the context of social relations 10 Mar 2016

The project examines the topic of Nonsuicidal self-injury (NSSI) in social context, utilising sociological methods and perspectives. Our approach has the potential to further develop knowledge in this area, by providing insight into how social relationships shape, and are shaped by, the practices and experiences of NSSI/self-harm. Our vital innovation will be to research not only those who do or have self-injure/d, but also those who hold / have held close relationships with people who self-injure/d. Investigating these two complementary viewpoints on NSSI will allow us to better understand the interaction between the practice and the relationships that it a/effects. We aim to conduct a one year pilot study, which will provide three key elements needed to build our larger research programme: (1) proof of concept regarding the contribution that sociological perspectives on relationships and social interactions can make to understanding NSSI, published in a position piece in a key sociology of health and illness journal (e.g. Social Science and Medicine or Sociology of Health and Illness); (2) refinement of our proposed methods for data collection and analysis in this sensitive area; (3) pilot data to inform applications for further funding, and ultimately develop a full research programme.

Amount: £44,882
Funder: The Wellcome Trust
Recipient: University of York

Systems Investigation of Germinal Centre Formation. 30 Jan 2015

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: £39,262
Funder: The Wellcome Trust
Recipient: University of York

Medical transformation in Madras Presidency: Military and Civilian perspectives (1890-1940) . 12 May 2015

1) An investigation into the growth of complexity of military medicine and the ways in which it shaped colonial medical policy. 2) An examination of military medicine as a laboratory of clinical, technological and public health innovations, including trials which were later expanded across colonial Madras. 3) An exploration of the transfer of techniques and technology considered successful in these contexts to the civilian medical sphere, through Indian Medical Service officials (in government - and privately-funded medicine). 4) An assessment of the variations within urban contexts, as well as urban-rural differences. Based on an analysis of discussions and debates between IMS and Subordinate Medical Service officials, as well as an analysis of official reports, medical journals and newspapers. 5) An investigation of what is best described as a counter-narrative of success, which often took the shape of arguments about the dangers, limits and expense of new technologies. An examin ation of how these influenced military, civilian, indigenous and European perceptions within Madras Presidency, in relation to what was classed by the colonial authorities as being cutting edge medical technologies and care protocols.

Amount: £123,582
Funder: The Wellcome Trust
Recipient: University of York

A critical management history of strategy and disease in the mining industry: a pilot survey of archives. 25 Nov 2014

This project will conduct a pilot survey of archives to establish the feasibility of conducting a critical management history of the effects of disease among miners in shaping corporate strategy in the mining industry. The literature on the social history of disease in the mining industry indicates that mining companies were aware of the significant medical problems among miners associated with mining (for example, by the diseases of silicosis and pneumoconiosis). However, the business and manag ement history of the mining industry (specifically that which deals with strategic management by senior executives) does not discuss the operational effects or the human costs of disease among miners. This project is aimed at beginning to address this gap in the historiography, to establish how strategy was made with reference to diseases associated with industrial working conditions in the mining industry. However, a possible barrier to this research is whether sufficient historical records are in existence to allow the project to be undertaken. This application for funding will facilitate a survey of archives to establish the extent and location of relevant archival materials on which further research could be based.

Amount: £4,353
Funder: The Wellcome Trust
Recipient: University of York

A Phase IIa/IIb clinical trial to evaluate the therapeutic efficacy of ChAd63-KH vaccine in patients with persistent post kala-azar dermal leishmaniasis (PKDL)” 14 Jul 2015

Translation Fund Award to Professor Paul Kaye, University of York Visceral leishmaniasis (or kala azar) is a chronic and life threatening parasitic disease caused by infection with Leishmania donovani and L. infantum. There are approximately 400,000 new cases each year, mainly in Sudan, South Sudan, India, Bangladesh, Ethiopia and Brazil, with a case fatality rate of ~10%. Although a handful of drugs are available, efficacy varies geographically and emerging drug resistance is a major threat. In East Africa and South East Asia, the lack of complete efficacy of these drugs can also lead to patients developing a chronic and stigmatizing skin disease, called post kala azar dermal leishmaniasis (PKDL). The development of new preventative and/or therapeutic measures to combat this infection is therefore a major international research priority. An international research team, funded by the Wellcome Trust and led by Professor Paul Kaye at the University of York, has developed a new adenovirus-based vaccine for visceral leishmaniasis, which has shown efficacy in animal models and safety and immunogenicity in a human Phase I clinical trial. This new study will allow the team to evaluate the vaccine for safety and therapeutic efficacy in Sudanese patients with persistent PKDL. The study will first identify a safe dose of the vaccine to use in adults and children with PKDL and then proceed to test whether a single dose therapeutic immunization can stimulate immune responses leading to clinical cure or reduction in symptoms. If successful, these clinical trials will determine whether therapeutic vaccination has the potential to be developed further, as an alternative treatment option for patients with PKDL and perhaps other forms of leishmaniasis.

Amount: £1,564,336
Funder: The Wellcome Trust
Recipient: University of York
Amount: £1,207,211
Funder: The Wellcome Trust
Recipient: University of York

A T cell receptor transgenic model for studying CD4+ effector and regulatory T cells in bacterial-induced colitis. 19 Oct 2006

The intestinal bacterial flora and the CD4+ T cell response to these bacteria play an important role in the induction and regulation of chronic intestinal inflammation. The process by which bacteria-specific CD4+ T cell responses are initiated, and the factors that determine pathogenic versus disease-protective CD4+ T cell effector choice, are however not well understood. The objectives of this project are to define the mechanisms by which specific bacterial antigen/CD4+ T cell interactions trig ger colitis in disease-susceptible hosts and suppress its induction in disease-resistant hosts. We will use a newly developed transgenic mouse model based on the T cell receptor of a disease-inducing CD4+ T cell clone specific for the flagellar hook protein (FHP) of Helicobacter hepaticus. This system will enable us to distinguish bacterial from host-directed immune responses and to study the development of pathogenic effector and disease-protective T regulatory (Treg) cells. The goals of the pr oject are to i) identify the process whereby FHP-specific CD4+ T cells trigger inflammation in the intestine of H. hepaticus-infected mice, ii) define the interaction between H. hepaticus and dendritic cells (DCs), and iii) determine whether mucosal DCs can induce the differentiation of FHP-specific CD4+ Treg cells.

Amount: £287,708
Funder: The Wellcome Trust
Recipient: University of York

Structure and mechanism of multicomponent protein-nucleic acid assemblies. 28 Mar 2007

The research will focus on analysing protein-nucleic acid interactions and related molecular events in the framework of large assemblies. Although the main emphasis is on X-ray analysis, several complementary techniques such as electron microscopy, mass spectrometry and analytical ultracentrifugation, which provide insight into the assembly s composition and the strength of interaction, will be involved. Key goals in the main projects: (1) To understand the structure-function relationship for several tRNA modifying enzymes. To characterize protein interactions with tRNA and determine the crystal structures of protein-tRNA complexes by the X-ray analysis. (2) To continue investigations into the mechanism of DNA translocation by double-stranded DNA viruses, using bacteriophage SPP1 as a model system. Determine the X-ray structure of viral ATPase, which powers DNA translocation, and prepare stable complexes and obtain structural information for the complex of ATPase with the portal pr otein and DNA. Use the derived structural data for understanding how chemical events during the ATP hydrolysis are linked to the mechanical events during DNA translocation. (3) To extend studies on the regulatory processes involving multisubunit proteins and multiple-repeated RNA segments, using B.subtilis TRAP/RNA/anti-TRAP as a model system.

Amount: £976,222
Funder: The Wellcome Trust
Recipient: University of York