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Results

Resolving the molecular architecture of human DNA lesion bypass machines 06 Sep 2018

DNA replication through regions of damage is termed translesion synthesis (TLS), a mechanism conserved from bacteria to mammals and executed by the interplay of high-fidelity and error-prone DNA polymerases, that latter of which can accommodate distorted templates in their active sites. Despite its major role in the maintenance of genome stability and implication in human cancer, TLS is still poorly understood at the molecular level. In this proposal, we will set out to unravel the molecular mechanisms of TLS. We will reconstitute, in vitro, two minimal replisomes including the human high-fidelity polymerase pol delta or the TLS polymerase pol eta. For the first time, we will employ cryogenic electron microscopy (cryo-EM) to determine these replisomes' structure. This work will constitute the critical building block for a far-reaching mechanistic investigation, which will combine cryo-EM and single-molecule fluorescence microscopy to resolve the architecture and choreography of the DNA lesion bypass machinery.

Amount: £95,982
Funder: The Wellcome Trust
Recipient: University of Leicester

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £22,238
Funder: The Wellcome Trust
Recipient: University of Leicester

Mask Sampling and the TB Aerosol: a new detection method and approach to transmission studies. 18 Feb 2015

Although Mycobacterium tuberculosis (Mtb) depends on aerosol transmission, the number of bacilli expectorated over time, diurnal variability and correlations with clinical features, are unknown. Infectivity assessed by sputum analysis provides a crude gradient of transmission risk but lacks predictive value. Cough Aerosol Sampling System (CASS) identifies transmission risk better than sputum analysis but do not directly capture infectious aerosols naturally. Mask sampling has potential as an am enable sampling system to aid understanding, management and ultimate control of TB and other airborne infections. Here, I will develop our established mask sampling approach to quantify Mtb aerosol output and characterise the production of Mtb, map diurnal patterns of aerosol production, determine relationships between Mtb in aerosols and concurrent sputum samples and the value of aerosol measurements as a marker of infectivity. I will optimise the sampling protocol and develop a standardised q uantitative molecular assay which will be applied to serial mask samples to assess the total daily aerosol output of Mtb, circadian variability and correlation with cough and clinical features. A comparison of the mask and CASS will provide reference to an established technique. Finally, I will use the TB Case Control Platform to relate mask results and transmission.

Amount: £296,393
Funder: The Wellcome Trust
Recipient: University of Leicester

Patient Safety: Looking Back, Going Forward. 31 Mar 2015

The General Medical Council (GMC) has launched a radical consultation this year, which will place patient safety at the heart of medical education and training across the UK. Even so, historically, it remains a neglected area of research in the medical humanities. This has created a policy vacuum and one that urgently needs to be filled by bringing together researchers, practitioners and patient groups to speak about how to maintain a safe environment for patients. Our proposed one-day workshop is therefore being convened in June 2015 at Leicester University at a critical time in patient-safety research and policy. It will be primarily for front-facing staff medical professionals, healthcare managers and patient groups confronted by the challenges of managing patient safety on a daily basis. Delegates will share the latest historical research during the workshop, to stimulate new conversations about how the lessons of the medical humanities can inform current practice. By way of examp le, we have attached one of the proposed planned break-out workshops. It is envisaged that this interactive format will lead to a larger grant application to the Wellcome Trust in the foreseeable future, with the primary purpose of bringing together various stakeholders in nationwide patient safety.

Amount: £2,450
Funder: The Wellcome Trust
Recipient: University of Leicester

A multi-user FACS facility at the University of Leicester 06 Jul 2017

We request funds to purchase a BD FACSAria Fusion cell sorter enclosed within a Class-II microbiological safety cabinet (MSC) to establish a multi user cell sorting facility. The FACSAria Fusion is a highly flexible and advanced flow cell based flow cytometer that can perform multi-parameter four-way sorting. The Aria flow cell-based detection method provides greater fluorescence sensitivity than alternative stream-in air based cell sorters, which is critical for many of the proposed studies. We have requested funds for a four laser (blue/red/violet/yellow-green) 18-parameter instrument to enable high dimension analysis of the cells during sorting. The violet laser will enable use of highly sensitive brilliant violet fluorochromes and the yellow-green laser will allow greater use of multiple fluorescent proteins. The instrument can also perform single cell index sorting into 384-well plates, which will enable our research teams to undertake single cell transcriptomics projects and sort CRISPR/Cas9-mediated gene edited cells. The instrument is fully integrated into the biosafety cabinet enabling work to be undertaken with primary patient samples and hazard group 2 pathogens. Maintenance, assisting new users and staff training are essential for such a complex instrument, we have therefore requested funding for an experienced grade 7 manager for a 4-year period.

Amount: £290,555
Funder: The Wellcome Trust
Recipient: University of Leicester

Unravelling Haemophilus influenzae and bacteriophage dynamics in the human upper respiratory tract 27 Apr 2017

Haemophilus influenzae is a pathogen that infect the human upper respiratory tract to cause diseases such as pneumonia and is associated with chronic diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) (Riesbeck, 2010). DNA sequence analysis of H. influenzae revealed the acquistion of novel genes mediated by phages which have not been identified; however, six H. influenzae phages have been identified of which HP1c1 is well characterised (Williams et al., 2002). The pathogen can change phenotype to escape HP1c1 but this makes it more vulnerable to the host immune system suggesting that phages impact the interaction of the of H. influenza with the host cell. During this project, we will isolate new H. influenzae phages from infected patients to better understand the pathogen dynamics in the respiratory tracts which could direct therapeutic towards treating these respiratory tract infections.

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

Evaluation of meningococcal disease isolates for phase variation in pilin adhesion determinants 27 Apr 2017

Neisseria meningitidis is the leading cause of bacterial meningitis. Carriage rates range from 10% for healthy populations to >30% in at risk populations. Invasive serogroup W (MenW) disease is increasing and has led to inclusion of MenACWY vaccine in the national immunisation schedule. Phase variation allows for alterations in outer membrane protein surface expression through slippage across simple sequence repeats (SSRs), altering the coding frame and truncating the protein or reducing promoter activity. Phase variation within pilC genes affects adhesion and virulence. Preliminary data demonstrates that phase variation is responsible for switching between pilC1 and pilC2 expression during carriage raising the potential for an impact on carriage to disease transitions. Key goals of this project are to analyse and compare phase variation in carriage and invasive MenW isolates. Objective 1: reconstruction of pilC loci through bioinformatics and PCR. Objective 2: analysis of variability in SSRs of pilC genes by alignments and GeneScan analysis. Objective 3: expression states of pilC1 and pilC2 will be determined through bioinformatics. Due to highly similar nature of MenW ST-11 genomes, these data will provide an excellent platform to study pilC phase variation within Neisseria and the effect upon bacterial adherence.

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

Healthy Citizens? Migrant Identity and Constructions of Health in Post-War Australia. 05 Aug 2014

Psychological and epidemiological frames dominate studies of migrant health in Australia, resulting in understandings of migrants as either possessing a physical health advantage or a propensity to mental health disorders. However, this project sees Australia's unique post-war migration revolution, in which 3 million British and European people relocated to the other side of the world, as an opportunity to examine how constructions of health, migrant identity and national identity are intricatel y linked. It will investigate these connections through an analysis of migrants' life writings, held in Australian libraries, museums and community archives, as well as through oral history interviews and material culture. To contextualise these experiences the project will trace medical professionals' perspectives on migrants' psychological and bodily health between 1945 and 1970; evaluate how constructions of Australia as a 'healthful haven' were harnessed by government bodies to attract new a rrivals; and assess how the doctrine of assimilation pervaded the delivery of health care and advice to migrants. In doing so it will demonstrate how an interdisciplinary approach to the history of medicine, encompassing medical literature, oral history and material culture, can better explain popular attitudes to health in the mid-twentieth century.

Amount: £162,171
Funder: The Wellcome Trust
Recipient: University of Leicester

Bridging the gap between patients and carers : The case of rare disease patient-advocacy actors. 22 Apr 2013

This project investigates the relationship between advocacy action and the empowerment of patient communities. Empowerment is here understood as patients participatory action in decision-making on disease research and treatment. The study specifically focuses on rare disease patient-advocacy actors because according to the scientific literature they are among the most empowered groups in the health sector and may serve as a model for other patient groups that are still struggling to get particip atory power in policymaking and research implementation. The project will develop four lines of investigation focused on specific elements of mobilization: [LI1] processes of information sharing among patients, health care professionals, institutions and policymakers; [LI2] lobbying strategies aimed at bolstering awareness in the institutional polity; [LI3] campaigning strategies aimed at generating awareness in the general public; [LI4] fundraising strategies aimed at generating economic suppor t for the development of drugs, treatments, and services. The investigation will examine a sample of rare disease patient-advocacy groups from the E.U. and the U.S. Web Content Analysis techniques (qualitative textual analysis combined with Hyperlink Network Analysis) will be used to study processes of information sharing, while interviews with organisation representatives will provide insiders information on lobbying, campaigning, and fundraising.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University of Leicester

Imperfect Children. 25 Mar 2013

This application is for a conference dealing with the concept of imperfection as it relates particularly to children. The word itself is contentious whether applied in a contemporary or historical sense. It assumes normative standards of behaviour, physical appearance, mental capacity or way of living. At the same time it means very different things in particular ethnic, geographical or historical contexts. Applied to children who are constantly developing their intellectual and physical capacit ies, physical appearance and other attributes, it is particularly contentious. During the conference we wish to explore the concept and language of imperfection. We also, however, want to look explicitly at some of the imperfections themselves. These might include, but are not limited to: Mental or physical impairment; physical appearance, and the desire to improve children; learning development, and diagnosing and correcting imperfection. It is anticipated that the papers will have an historica l focus or will link historical data/perception with twenty-first century concerns. However, several of the papers offered for the conference meld historical perspective with methods and sources drawn from archaeology, art history, sociology and English literature. Two of the papers are by scientists working in the biological sciences, as the more detailed description shows.

Amount: £1,728
Funder: The Wellcome Trust
Recipient: University of Leicester

Biomedical Vacation Scholarship. 24 Jun 2013

Not available

Amount: £10,980
Funder: The Wellcome Trust
Recipient: University of Leicester

Open access award. 20 Sep 2011

Not available

Amount: £60,000
Funder: The Wellcome Trust
Recipient: University of Leicester

Women Surgeons in Britain, 1860-1918. 08 Jun 2011

This project has a dual intention. Firstly, to examine the cultural, social and self-representation of the woman surgeon from the second half of the nineteenth century until the end of the Great War; and, secondly, to investigate precisely what surgery women actually performed during this period. In doing so, I aim to bring together and expand upon work on the history of women in medicine (particularly that by Mary Ann Elston), the history of surgery (Christopher Lawrence; Peter Stanley; Sally W ilde), and feminist historical studies concerning women's place in Victorian and Edwardian society (Philippa Levine; Anne Witz), in order to offer a new perspective on the questions provoked by medical women. By utilising a wide variety of sources, including visual representations of female surgeons and a wealth of unpublished material, such as hospital records, case notes, and correspondence, I intend to provide a wide-ranging history of women surgeons and their social, political and medical im pact between 1860 and 1918.

Amount: £108,343
Funder: The Wellcome Trust
Recipient: University of Leicester

Reviewing the occupational risks of sex workers in comparison to other ‘risky’ professions: mental ill-health, violence and murder. 03 Oct 2015

Bringing together social scientists, epidemiologists and health practitioners, this project aims to understand how occupational health and safety differs between sex workers and other professions which are established as ‘risky’ because of the elevated prevalence of violence in the workplace and poor mental health. Through literature reviews and evidence scoping, we will examine and synthesize data on the occupational risks of sex workers (female, male and transgender) across street and indoor workplaces in comparison to ‘risky’ professions as categorised by the occupational literature, focusing on three key areas: mental ill-health, violence and murder. We will analyse routine data gathered by our research partners National Ugly Mugs, to better understand the risk, forms and circumstances of murders and violence committed against sex workers in the UK, and integrate these analyses with the literature review findings. This knowledge will expand our understanding of the role of the workplace in shaping and protecting against risk, and our capacity to develop policies and practices that address specific occupational health inequalities faced by sex workers. Our dissemination plans will establish a network of multidisciplinary researchers and practitioners to develop research projects and impact activities to improve the health and safety of sex workers.

Amount: £30,712
Funder: The Wellcome Trust
Recipient: University of Leicester

Combat Exhaustion and Demobilization in the United States, 1941-50. 23 Mar 2007

Combat Exhaustion and Demobilisation in the United States, 1941-50 This proposed research project examines the relationship between medicine and psychiatry within the context of US involvement in World War II. The project will consider particularly the influence of new psychiatric nomenclature in terms of the treatment of illness and injury in World War II, with new terms such as 'combat exhaustion' and 'operational fatigue' replacing the 'shell shock' of World War I. My focus will be on induction procedures in the US armed forces for assessing the mental and physical health of recruits and on the rehabilitation of war casualties. My project will also examine (i) the medical-psychiatric interface by analysing clinical literature and reports written during and immediately after World War II and (ii) how combat exhaustion was represented in the cultural sphere, both in terms of training films made by the US Medical Army Department and the cycle of commercial 'demobilisation films' that were produced between 1946 and 1950. My concern is centrally with the US involvement in World War II, but I will consult British and Canadian military psychiatric texts and assess the changing psychiatric terminology with reference to World War I and the Korean War in the early 1950s.

Amount: £2,750
Funder: The Wellcome Trust
Recipient: University of Leicester

Confocal imaging of intracellular protein dynamics. 17 Oct 2005

For many processes in cell biology, the key proteins involved have now been identified. Yet we remain far from understanding how these proteins function because information on how they respond to different cellular cues and interact on a temporal and spatial basis in vivo is lacking. We propose to use state-of-the-art imaging technology to tackle this problem through experimental observation of the localization, interaction and dynamics of proteins in living cells. We will specifically examine the assembly and organization of subcellular macromolecular machines including the centrosome, focal adhesion complexes, signalling pathway scaffolds, spliceosomes and the nuclear envelope. This will complement and enhance Wellcome Trust funded projects in each of these areas. To make a real impact, we request funding to purchase a Leica AOBS laser scanning confocal fluorescence microscope with appropriate lasers and software modules that will enable us to perform quantitative, multiwavelength, time-lapse imaging, FRET and photobleaching studies. The requested equipment will be incorporated into the epifluorescence microscope facility set up in Leicester with funding from the Wellcome Trust in 2001 and managed by the grant-funded technician. This will provide us with an entirely new range of imaging technologies enabling us to remain internationally competitive in our research areas.

Amount: £233,102
Funder: The Wellcome Trust
Recipient: University of Leicester

Structures, functions and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors: a detailed understanding of the molecular basis of tuberculosis pathogenesis and importance of pathogen to host 06 Jul 2006

Tuberculosis remains the most significant bacterial infection of humans, leading to over 2 million deaths annually. The recent availability of complete genomes for M. tuberculosis and several closely related mycobacterial pathogens has catalysed work on the molecular basis of tuberculosis pathogenesis, resulting in the identification of a significant number of novel proteins clearly linked to virulence. The overall aim of the proposed programme is to obtain a detailed molecular understanding of the roles and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors, with a particular emphasis on secreted proteins involved in pathogen to host cell signalling. The proposed work will focus on three related areas: i) Continued investigation of the precise roles and mechanisms of action of the CFP-10.ESAT-6 complex and MPB70, with key goals including identification of host cell receptors and assessment of the importance of specific signalling pathways in mediating host cell responses. ii) Characterisation of the structures, functions and mechanisms of action of other members of the ESAT-6/CFP-10 family, such as Rv0287/Rv0288, with key aims including identification of host cell target proteins and determination of the rules governing complex formation. iii) Determination and analysis of high resolution structures for the novel proteins encoded by the Rv3613c-Rv3616c operon, with key goals including the identification and assessment of possible functional sites and mechanisms of action.

Amount: £494,192
Funder: The Wellcome Trust
Recipient: University of Leicester

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £8,640
Funder: The Wellcome Trust
Recipient: University of Leicester