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Funders:
The Wellcome Trust

Results

Investigating the phenotype, function and interactions of tissue-resident B cells 30 Sep 2016

Tissue-specific immunity is shaped by the local milieu. In organ systems that interface with the environment (e.g. skin, gastrointestinal tract), exogenous signals generated by commensals or diet can profoundly influence resident immune cells. In non-interfacing tissues (e.g. kidney), endogenous signals such as interstitial osmolality may also influence the immune landscape. Tissue epithelial cells play an important role as environmental sensors and may instruct local immune responses. In addition, environmental cues may be directly detected by resident immune cells. To date, studies of tissue sentinels have focused on innate immune cells and on T cells with limited data on B cells. We have preliminary data from human and murine kidneys, and from human liver tissue and murine bladder tissue demonstrating the presence of tissue-resident B cells. In humans, they are predominantly of a memory phenotype. We hypothesize that tissue-resident B cells make an important contribution to local immune responses and that their localization and function will be determined by tissue-specific environmental cues. This project aims to investigate the phenotype of these tissue resident B cells (both in mouse and human), their antigenic specificity, origin, function and interaction with other cells.

Amount: £235,304
Funder: The Wellcome Trust
Recipient: University of Cambridge

Primate lentiviral Vpx: insights into DNA sensing and zoonotic potential 30 Sep 2016

Innate detection of cytoplasmic DNA is central to human health and disease. DNA sensor cGAS and adaptor protein STING represent a key pathway. On recognition of viral cytoplasmic DNA, cGAS produces a secondary messenger that activates STING. This initiates signalling that stimulates transcription factors IRF3 and NF-kB and an inflammatory response. I have discovered that lentiviral accessory protein Vpx, expressed by zoonotic HIV-2 and related lentiviruses, is a DNA sensing antagonist. I have shown that Vpx selectively inhibits NF-kB, but not IRF3, activation downstream of cGAS/STING. I propose that Vpx is a tractable tool to interrogate the molecular mechanisms of DNA sensing that underpin diverse infectious and immune pathologies. Furthermore, Vpx allows examination of the central role for DNA sensing as a barrier to zoonosis. My specific objectives are: 1. To characterise the mechanism of Vpx inhibition of NF-kB activation. 2. To use SILAC to identify novel Vpx-host factor interactions occurring specifically after cGAS activation. 3. To characterise Vpx proteins from zoonotic and non-zoonotic simian lentiviruses, and epidemic and non-epidemic HIV-2, with a view to understanding the role of DNA sensing antagonism in cross-species lentiviral transmission. This fellowship will produce critical insight into central biological pathways of emerging medical importance.

Amount: £241,313
Funder: The Wellcome Trust
Recipient: University College London

Cognitive Factors in Adjustment to Social Trauma 30 Sep 2016

Socially traumatic events that may include rejection or humiliation in the context of bullying can have lasting and debilitating psychological effects. This project will investigate the nature of these effects, explore maintaining mechanisms of psychopathology, and develop and pilot a specific intervention to improve functioning in adults suffering after experiencing social trauma. It will build on cognitive models and existing treatments for posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD). First, there will be a detailed investigation of social trauma and its effects in young people using surveys, interviews, and secondary analyses of cohort data. Negative effects may include intrusive memories, negative appraisals of self and others, safety behaviours, and disrupted post-event processing. The nature of psychopathology related to social trauma will be validated against existing measures of PTSD, SAD, and depression. A series of experimental studies on appraisals of social threat and qualities of social interactions will distinguish those struggling more and less severely after social trauma and fulfil the second goal of identifying maintaining mechanisms. The final goal is to develop and evaluate a procedure for updating problematic social trauma memories in a pilot case series. Overall, this project will help improve psychological treatments following social trauma.

Amount: £247,640
Funder: The Wellcome Trust
Recipient: University of Oxford

Targetting optogenetic constructs to retinal ON-Bipolar cells 30 Sep 2016

"How best can optogenetic constructs be targeted to retinal ON-Bipolar cells to restore functional vision?" This project aims to use the human photopigment melanopsin to induce light responses in retinal ON-bipolar cells (optogenetics) of a mouse model, blind from retinal degeneration, in order to restore functional vision. This comprises three key goals: Goal 1 "When" To further describe changes in bipolar cells over time during retinal degeneration in terms of their gene expression and association with other cells in the mouse model. Goal 2 "What" To determine if melanopsin - or an alternative construct (Channel Rhodopsin - ChR2) - is more efficacious in restoring functional vision. Quantified:- At a cellular level (Calcium imaging, Electrophysiology) At an organism level (Behavioural paradigms) Goal 3 "Where" To determine if bipolar cells – or an alternative target (retinal ganglion cells) - are more efficacious in restoring functional vision by melanopsin expression (quantified as in goal 2). The eventual purpose of these goals is, along with parallel work, to develop an application to the Gene Therapy Advisory Committee (GTAC) to conduct a clinical trial to restore functional vision in patients blind from inherited retinal degenerations.

Amount: £285,040
Funder: The Wellcome Trust
Recipient: University of Oxford

Health Priorities in Resource Limited Settings 30 Sep 2016

Liverpool Clinical PhD Programme: Health Priorities in Resource Limited Settings

Amount: £76,325
Funder: The Wellcome Trust
Recipient: University of Liverpool

Health Priorities in Resource Limited Settings 30 Sep 2016

Liverpool Clinical PhD Programme: Health Priorities in Resource Limited Settings

Amount: £66,091
Funder: The Wellcome Trust
Recipient: University of Liverpool

Optimising antimicrobial therapy for sepsis in Malawi 30 Sep 2016

Mortality from severe sepsis in Malawi is extremely high – 50% compared to 20-30% in high-income settings. Guidelines on optimal use of available therapies (antimicrobials, intravenous fluids and oxygen) are extrapolated from high-income settings and/or based on expert opinion. Data to inform acute care guidelines for Malawi and sub-Saharan Africa (SSA), are urgently needed. Data from SSA suggest sepsis is caused by diverse pathogens including M. tuberculosis, not covered by current empiric therapy, and I propose that broadening the spectrum of empiric antimicrobial chemotherapy may play a role in improving outcomes. Great care must be taken with such a strategy to minimise development of antimicrobial resistance (AMR). The epidemiology of this emerging threat is not well understood in Malawi, but longitudinal surveillance reveals an alarming increase in drug resistant infection. I propose to: Conduct a prospective case-cohort study of severe sepsis patients in Malawi to provide a detailed description of sepsis, including microbiological causes and determinants of poor outcome. Use deep sequencing to study survivors and describe acquisition and duration of carriage of resistant bacteria. Ultimately, this will guide antimicrobial strategies to achieve the twin aims of improving clinical outcomes while minimising the development of AMR in Malawi.

Amount: £396,007
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Functional genomics of malaria sporozoite - host hepatocyte interactions 18 May 2016

Intensive study of the ligand-receptor interactions by which malaria merozoites invade erythrocytes has yielded promising vaccine and drug targets. In contrast, there is little understanding of the process by which malaria sporozoites invade hepatocytes, despite the fact that antibody-inducing sporozoite-targeting vaccines are the leading approach to malaria vaccine development. I propose to use the following recently developed and complementary techniques to systematically elucidate ligand-receptor interactions involved in this process: 1. Biochemical identification of ligand-receptor interactions using an existing library of pentameric P. falciparum sporozoite proteins to probe plate-anchored recombinant hepatocyte surface proteins. 2. Genetic identification of receptors essential for in vitro hepatocyte invasion using a CRISPR-Cas9 gene-disruption strategy. A lead panel of 100 abundant candidate receptors will be selected using existing proteomic data, with potential for extension to the complete hepatocyte surface proteome. Identified interactions will be validated via host and parasite manipulations (gene disruption and antibody blockade), both in vitro using primary hepatocyte cultures and in vivo, including use of a humanized mouse model of P. falciparum liver-stage infection. As has been the case for study of merozoite-erythrocyte interactions, I anticipate the project will provide the basis for rational approaches to malaria prophylaxis via disruption of the identified interactions.

Amount: £414,492
Funder: The Wellcome Trust
Recipient: University of Oxford

Public Engagement Provision 31 Dec 2015

Not available

Amount: £4,938
Funder: The Wellcome Trust
Recipient: University of York

Provision for Public Engagement 31 Dec 2015

We will exploit our discovery of fundamental mechanisms regulating assembly in important single-stranded RNA viruses based on multiple, dispersed RNA-protein interactions (packaging signals, PSs) to: 1. Determine how genomic RNAs play regulatory roles in the mechanisms of virus assembly, maturation and host cell invasion. 2. Determine which viral and host components are needed to develop a quantitative systems understanding of assembly in vivo. 3. Analyse how viruses may evade anti-viral strategies targeting PS functions, triggering the occurrence of mutant strains. This paves the way for novel forms of anti-viral intervention.

Amount: £4,937
Funder: The Wellcome Trust
Recipient: University of Leeds

Characterisation of innate immune DNA sensing and viral evasion strategies 15 Sep 2016

We have identified an entirely new mechanism by which retroviruses regulate the process of DNA synthesis. We have discovered that, contrary to textbooks, the process of HIV-1 DNA synthesis occurs inside intact capsids and that the nucleotide fuel for DNA synthesis is sucked through regulated electrostatic channels formed by the hexmaeric capsid lattice making up the viral core. We have also discovered that the channels can open and close through a molecular iris formed by the capsid beta hairpin sequences at the 6-fold access of symmetry. This work is in press in Nature. Preliminary data suggest that non-pandemic forms of HIV do not properly regulate their capsid pores and that this causes these viruses to be less able to evade intracellular innate sensing mechanisms. This may explain their failure to reach pandemic levels of human-to-human transmission. Our current work aims to understand the molecular details of how pandemic HIV-1 regulates DNA synthesis through cofactor recruitment and regulation of the capsid channels. We also aim to understand whether the non-pandemic viruses also do this and to understand what features they lack. We also aim to understand when the process of channel regulation evolved, ie in the parental chimpanzee viruses or in humans as HIV-1.

Amount: £24,874
Funder: The Wellcome Trust
Recipient: University College London

Everyday Cyborgs: Stories from Inside Out 31 Oct 2015

'Animal, Machine and me' is a sociological investigation into modern practices that repair and replace the human heart serves as a study in its own right but also one that has implications for developments in xenotransplantation and implantable technologies more generally. Utilising a case study approach three areas have been identified as contributing to the construction of stories or biographies of the implanted heart. These are 1) decision-making processes around porcine, bovine or mech anical aortic heart implants 2) recipient experiences of ICDs and 3) TAHs as an example of technological development in the area of whole organ replacement. A multi-method approach is indicated and will be conducted at various sites in the UK and the US. Envisaged outcomes are: increasing understanding of both clinical and non-clinical factors influencing the choice of animal or mechanical implants; reasons for psychosomatic side-effects in ICD patients and a review of the various factors invo lved in developing TAHs. There are therefore two transitions under scrutiny; the material from animal to human and the technological from implant to device to whole organ. Future research will seek to add an epidemiological strand by investigating the political economy of implants in developing countries

Amount: £35,050
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Infectious disease engagement activities in Sierra Leone during the post-Ebola recovery period 24 Feb 2016

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 use cutting 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 mutations on 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 have anti-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: £59,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The demand for prevention in middle and later life 18 Jul 2016

Population ageing is likely to increase the burden of non-communicable diseases (e.g. cancer). Prevention (including health behaviour and screening programmes) can considerably reduce the morbidity and mortality risks of these diseases, and will therefore play a key role in maintaining the health of an ageing population. The research project will investigate the demand for prevention among middle-aged and older people theoretically and empirically. In the first part of the project, I will derive a theoretical framework based on the health capital model that allows me to derive hypotheses on determinants of the demand for prevention, in particular with respect to time costs. In the empirical part of the project I will test these hypotheses using econometric methods for causal inference and data from the UK as well as international data. I will analyse three specific factors that are associated with different levels of time costs and play a major role among older people – retirement, informal care provision and voluntary work. The projected output will consist of at least four academic papers and a number of conference presentations. I will engage members of the public in an advisory group. Keywords: prevention, screening, health behaviour, causal inference, ageing

Amount: £176,150
Funder: The Wellcome Trust
Recipient: University of Oxford

Material Anxieties: The Perceived Health of Materials in Medical Products 11 Jan 2016

This project will study the dynamic trajectories of materials like stainless steel, silicone rubber and PVC that make up clinical and direct-to-consumer healthcare products. I will follow materials as they move from manufacturing to the marketplace and beyond, exploring their perceived risks and rewards, and examining how the choices of materials scientists and designers influence users’ experiences of health and wellbeing. The project’s innovative tripartite method will afford a uniquely holistic understanding of human experiences of materials, combining ethnography, design research and psychophysics to allow for a simultaneous focus on the physical, sensory, aesthetic and cultural affordances of materials. My key goals are to firmly establish this new interdisciplinary approach, thereby providing a bridge between the laboratory, design studio, care environment and society, with the potential to influence design practice, research directions in materials science and practices and experiences of healthcare. In bringing together materials producers, designers, clinicians and users this project encourages dialogue and enables translation between isolated disciplinary and professional communities. It therefore takes crucial first steps towards the identification and development of materials that accord with clinical and societal needs.

Amount: £200,556
Funder: The Wellcome Trust
Recipient: University College London

Technological change and the health and wellbeing of youth: A case study of gambling 13 Jan 2016

Britain has one of the most diverse and accessible gambling environments in the world and has one of the most developed digital landscapes in Europe. The intersection of gambling provision with various digital products creates new risk environments for youth. Over 1 million adults are at-risk of harm from their gambling, with youth being at greatest risk of problems. It is timely to explore the impact of expanded (online and offline) gambling provision upon the health and wellbeing of youth as this cohort have grown up within a vastly altered gambling and digital landscape. Using qualitative and quantitative longitudinal methods, secondary analysis and case studies of industry practice, this study will: investigate changes in the relationship between youth gambling behaviour and use of digital technology. explore how young people’s perceptions of and engagement in gambling are shaped, focusing on the role of digital technologies and digital engagement as determinants of gambling initiation and behaviour change. examine the role of corporate action in the creation of ‘risk’ environments for youth by critically examining corporations’ practices. By exploring convergent gambling and digital development insight will be gained into the impact of this broad societal change upon the health and wellbeing of youth.

A Study in Specialism: cataloguing and conserving records of St Mark’s Hospital 18 May 2016

To catalogue and conserve records of St Mark’s Hospital, and related bodies, resulting in a complete catalogue of this unique collection, to enable its promotion and use as a resource for research into the history of medicine and healthcare policy in the 20th-century. Key goals for the project include: 1) the preservation, cleaning, and repackaging of unique archival records to better ensure their stability and long-term survival. 2) the compilation of a detailed catalogue of all project material and making that information available to researchers via a hosted website. 3) the conversion of audio recordings to a digital format to ensure their long-term preservation and access, and the digitisation of selected images from the St Mark's photographic collections. 4) public and academic outreach activities to highlight the research value and wider interest of the collection 5) the implementation of archival transfer and retention arrangements for the post-1995 records of St Mark's Hospital

Amount: £104,156
Funder: The Wellcome Trust
Recipient: Barts Health NHS Trust

William Hunter's Library: a transcription of the early catalogues 18 May 2016

This project will transcribe and produce an accessible digital version of one of the earliest manuscript catalogues of William Hunter’s Library. Renowned as one of the finest 18th century libraries to remain intact and a keystone of Hunter’s collecting, the main goal is to create a tool to enable efficient and in-depth analysis of his original book collection. The project will harness the flexibility and power of a collections management system (CMS) to provide public digital access to a fully searchable modernised version of a manuscript catalogue of Hunter’s Library dating from 1785, linking to current catalogue records and facsimile images of pages from the original volume/s. Our ultimate objective is to create a portfolio of new resources (Digital Hunter) that will break down traditional divisions that have hindered intellectual access to Hunter’s collections as a whole. A thorough understanding of the contents of Hunter’s Library – what texts he acquired, read and was influenced by – is key to our understanding of him as a physician and medical educator who desired to create a 'factory of knowledge'. This project will thus support future inter-disciplinary research in re-evaluating Hunter as an important figure in Enlightenment society.

Amount: £58,998
Funder: The Wellcome Trust
Recipient: University of Glasgow

Inside Medical Science: Conversations with Experts 18 May 2016

Oxford Brookes University is the custodian of the Medical Sciences Video Archive, a collection of 287 video recorded interviews with prominent figures in medicine created between 1985 and 2002. The collection is unique and represents the only recorded interviews with prominent figures from medical science, including a selection of Nobel Prize winners. At present the collection is trapped in legacy formats that do not allow for wider dissemination and use. The University proposes to digitise the recordings and make them openly available on the web. The imperative for digitising the collection is driven by two factors; increasing access to the recordings, and enabling their long-term preservation. Digitisation will address both of these issues, ensuring that the materials have as wide an impact as possible, and guaranteeing their on-going preservation beyond the life of the current physical media on which they are stored. The collection will be made available online, with no restrictions on access, via Oxford Brookes University's Research Archive and Digital Asset Repository (RADAR). A dedicated collection and associated web pages will be created. Long-term preservation, curation and secure storage of the digitised collection will be delivered by the Arkivum service currently in use at Oxford Brookes University.

Amount: £38,801
Funder: The Wellcome Trust
Recipient: Oxford Brookes University

Transform the Walgreens Boots Alliance Collection from a predominantly internal service to an international academic resource - phase II 18 May 2016

The purpose of this project is to transform the current archive facility from a predominantly internal service to an internationally accessible research resource. The first stage of this project, which involves re-cataloguing the entire collection to create an ISAD (G) compliant on-line catalogue, is successfully underway. The second stage of the project, as outlined in the initial application, is concerned with the long term preservation and accessibility of the material for researchers. This project will include all the paper records within the Walgreens Boots Alliance Archive, ensuring they are appropriately housed and in a fit state for consultation. Having taken full account of the preservation survey, produced following the scoping award, and having reviewed a number of different options regarding the most cost effective approach, it is proposed that the following activities are carried out: Purchase of a range of archive packaging materials to replace all non-standard folders and boxes. Recruit a newly qualified paper conservator to replace all non-standard packaging, create bespoke outers where needed, embed best practice within the team and help create a suite of best practice policies. Engage external consultants to advice on the long term storage solutions for the mixed media material within the collection.

Amount: £106,188
Funder: The Wellcome Trust
Recipient: Boots UK Ltd