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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University of Leicester
Amounts:
£500 - £1,000

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Results

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

Assessing Real and Perceived Barriers to Innovative Medical Practice 10 Nov 2016

This scoping exercise is to explore perceived barriers to clinical innovation in medical practice. This important area has recently been brought into sharp focus by Lord Saatchi’s Medical Innovation Bill, as well as government initiatives such as the Innovation Pathway for NHS Products and the Early Access to Medicines Scheme. It became clear from a Department of Health consultation that no research had been conducted into what barriers to innovation exist, or are perceived to exist by health professionals. The award would support the running of five focus groups to ascertain what doctors themselves see as barriers to the use of responsible innovative practices, and how they might be removed without compromising patient safety. The findings will underpin a bid for a larger, more comprehensive international project which will fully explore in detail real and perceived barriers to innovation. Key goals include building an evidence base identifying barriers and constraints to innovation, and whether these differ between or are specific to certain specialties. We also aim to establish a network of potential participants for the larger project, as well as strengthening our ability to collaborate and work as a team using a smaller, more manageable data set.

Amount: £35,738
Funder: The Wellcome Trust
Recipient: University of Leicester

Prefrontal control of hypothalamic feeding circuits: Balancing executive control of eating 05 Sep 2017

It is thought that diminished or excessive control over the drive to eat witnessed in eating disorders results from under- or over-activation of prefrontal cortical (PFC) brain regions important in decision-making. To investigate the executive control over eating this project aims to link the underlying circuitry between the PFC and feeding-promoting circuits of the hypothalamus to eating. Novel circuit-mapping strategies will be implemented to determine the functional relation between the two structures. This information will set the groundwork for relating PFC and hypothalamic activity in a rodent eating disorder model that promotes under- or over-eating. By consisting of two phases, one where animals restrict their food intake, the other where they over-consume food, we will monitor and relate changes in PFC and hypothalamic activity across phases where animals exhibit distinct feeding patterns. Finally, we will attempt to normalise this under-/over-eating by manipulating prefrontal inputs to the hypothalamus, thus determining a causal role for this circuit in influencing eating. In addition to linking executive circuits with feeding circuits this project aims to provide insight into the neural mechanisms underlying maladaptive eating behaviour.

Amount: £98,972
Funder: The Wellcome Trust
Recipient: University of Leicester

Cardiac rest and stress metabolism in patients with type 2 diabetes 12 May 2017

Patients with T2D are at significant risk of developing heart failure and related complications. Altered myocardial fuel selection may play a central role in cardiac disease risk in patients with T2D, by affecting myocardial oxygen demand and metabolic flexibility. At any given level of cardiac work, an increased dependence on fatty acids (FA) relative to carbohydrates decreases cardiac efficiency, which may adversely affect cardiac function. Overall Aim: To evaluate, in vivo, the effect of T2D on myocardial energy metabolism and metabolic flexibility. Hypothesis: In patients with T2D i) myocardium is metabolically inflexible with a fixed FA preference and inability to increase glucose utilisation even in response to acute increases in cardiac workload; ii) the fixed preference of FA utilisation significantly contributes to abnormalities in contractile function. Methods: Cross sectional, case-control study. Population: 22 T2D patients and 22 non-diabetic individuals with preserved cardiac function. Investigations: Significant coronary artery disease will be excluded in all patients by coronary angiography. Myocardial metabolism will be determined at baseline and during dobutamine stress with measurement of transmyocardial arteriovenous differences of oxygen and metabolites. Participants will undergo a comprehensive evaluation of cardiac structure, function and perfusion using rest and dobutamine stress CMR.

Amount: £60,923
Funder: The Wellcome Trust
Recipient: University of Leicester

Vacation Scholarships 2017 - University of Leicester 16 Jun 2017

Vacation Scholarships 2017 - University of Leicester

Amount: £11,500
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

Interaction of the NuRD corepressor complex with chromatin 27 Apr 2017

Histone deacetylates (HDACs) are important enzymes that play an essential role in cell development and differentiation. HDACs function as part of large protein complexes that are recruited to chromatin to regulate gene expression. The NuRD complex is one of these HDAC-containing complexes, of which the core protein components are known, but the mechanism of recruitment to chromatin is unclear. Our understanding of recruitment to the genome will be enhanced by structural and functional studies on a dimer of NuRD proteins, RBBP4 and MTA1. The MTA1:RBBP4 dimer has been shown to bind to chromatin through parts of the unstructured amino-terminus of histone H3. RBBP4 has also been shown to bind to the transcription factor FOG1 through an amino-terminal motif that is highly conserved in several other transcription factors including BCL11B and SALL1. In this project we propose to purify the MTA1:RBBP4 dimer from mammalian cells and then investigate the tightness of binding to fluorescently labelled peptides using fluorescence anisotropy. We will also set up crystallisation trials to gain structural insight into the mode of binding of these peptides to the MTA1:RBBP4 dimer.

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

Identification of novel Sin3A ‘proximate’ proteins and substrates using Biotin-ID 27 Apr 2017

HDAC1 and 2 (HDAC1/2) form the catalytic core of four co-repressor complexes (Sin3A, NuRD, CoREST and MiDAC) which have essential roles in DNA replication, cell cycle progression and gene expression. The goal of the Cowley lab is to define a network of accessory proteins, target genes and substrates (including non-histones), for each of the four canonical HDAC1/2 complexes. In this application we intend to contribute to this process by identifying novel associated proteins and substrates of the prototypical HDAC1/2 complex, Sin3A, using a new technique termed, Biotin-ID (Bio-ID). Bio-ID uses a promiscuous version of the biotin ligase, BirA (BirA*), fused to the protein of interest, thus allowing ‘proximate’ proteins (within approx. 10nm) to be labelled with Biotin, which can then be identified using a streptavidin pull-down and mass-spectrometry. The advantage of this approach is that it allows the identification of both binding partners and transiently associated proteins such as substrates. A parallel study with the LSD1/CoREST complex in the Cowley lab has identified known binding partners (CoREST1-3, HDAC1/2, and BHC80), substrates (p53), as well as 23 other novel chromatin associated proteins. We would therefore like to extend this approach to the study of the Sin3A/HDAC1 complex.

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

Single molecule analysis of DNA bending by the human mitochondrial transcription factor A (TFAM) 27 Apr 2017

Visualization of the dynamics of transcription initiation by mitochondrial RNA polymerase in real-time performed at single-molecule resolution forms the basis of this proposal. The human mitochondrial transcription factor A (TFAM) carries out DNA bending and my aim is to investigate whether this is an essential feature for transcription initiation by mitochondrial RNA polymerase. Multi-colour single-molecule super-resolution microscopy is the technique which will be used to demonstrate whether this DNA bending phenomenon is required for transcription initiation. This is a high-throughput technology capable of visualising reactions at single-molecule level, especially transcription factor binding, DNA bending and production of RNA. This state-of the-art instrument makes use of three different colours for accurate detection; green and red for smFRET and blue for RNA. I am also intrigued and have a desire to investigate for the first time whether DNA bending by TFAM is correlated with transcription by mtRNAP molecules.

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

CARD9 Modulation of IgA Stimulation of Human Mesangial Cells 27 Apr 2017

IgA nephropathy (IgAN) is, globally, the most common primary glomerulonephritis, and is characterised by the deposition of IgA in the renal mesangium resulting in mesangial cell proliferation and extracellular matrix synthesis. The condition has a variable prognosis; the severity of which does not correlate with the extent of IgA deposition. An IgAN genome wide association study identified a risk haplotype in the coding region of the non-redundant innate immune system protein, CARD 9. CARD 9 is known to play a pivotal role in the pathways linking extra cellular and intracellular stimulus to the production of pro-inflammatory cytokines. A number of groups have shown human mesangial cells (hmc) produce pro-inflammatory cytokines, when incubated with IgA in vitro. The Leicester group has also shown increased expression of CARD 9 in these cells and renal biopsies from patients with the more severe from of IgAN. This project will: 1. Investigate changes in CARD9 expression by hmc afer incubation with serum IgA1 IgAN patients and healthy controls. 2. Investigate changes in cytokine synthesis by hmcs incubated with IgA1 with and without CARD 9 siRNAs; 3 .Determine if spleen tyrosine kinase has a role to play in CARD 9 mediated IgA1 stimulation of hmcs.

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

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £900,000
Funder: The Wellcome Trust
Recipient: University of Leicester

Large-scale genomic epidemiology approaches to study the natural history of lung function and COPD 05 Jul 2016

Whilst risk factors for COPD are known, the determinants of lung function, COPD susceptibility and progression of COPD are incompletely understood. More effective approaches to prevention and treatment are urgently needed. We discovered genomic variants at many independent loci associated with lung function and risk of COPD. We and others have developed genomic epidemiology resources of unprecedented size utilising genome-wide genotyping arrays. Combined with genome-wide imputation, new statistical genetic approaches and epidemiological studies with measured lung function and electronic medical records we will advance understanding of the associations known to date and generate novel discoveries. We will fine-map loci to inform functional studies and study pleiotropic effects of associated variants. Using risk scores of variants showing genome-wide association and also genome-wide polygenic risk scores, we will assess the potential for improved prediction of COPD. We will develop methods to make more complete use of electronic medical record data and apply these in UK Biobank to boost the power to study disease relevant phenotypes. We will harness UK Biobank and large consortia to facilitate subgroup analyses at scale to generate novel insights into clinical heterogeneity in the natural history of lung function, COPD susceptibility and progression of COPD.

Amount: £1,318,502
Funder: The Wellcome Trust
Recipient: University of Leicester

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £38,204
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

Interaction between attentional signals and dopamine error prediction: focus on midbrain dopaminergic projections to prefrontal cortex. 08 Apr 2016

Midbrain dopamine is implicated in motivation and attentional processes related to error prediction. However, the dominant model of dopamine error prediction advanced over the last two decades is at odds with key behavioural observations and recent theories of attention suggest a role for top-down cortical control over error prediction. This leaves open the question about how the dopamine signal interacts with these top-down mechanisms. This proposal exploits recent advances in optical approaches to brain function which now make this question tractable using rat behavioural tasks. Firstly, I will use fibre photometry to record from dopaminergic projections to medial prefrontal cortex in a classical discrimination task. I will determine whether, in contrast to the canonical dopamine error prediction model, these projections represent both positive and negative prediction error with increased activity. Secondly I will carry out a causal experiment using optogenetic inhibition of prefrontal vs. nucleus accumbens dopaminergic projections in a blocking behavioural paradigm. This experiment will determine whether these projections differ in their contributions to error prediction. This work will delineate novel mechanisms of dopamine reward prediction with implications for our understanding of the fundamental nature of attention and motivation.

Amount: £99,962
Funder: The Wellcome Trust
Recipient: University of Leicester

Health communication for Chinese migrant mothers in northern England – an explorative qualitative study 30 Apr 2016

This study intends to make a contribution to researching the provision of maternal service to Chinese migrant mothers which is currently lacking in the health research literature. It explores mothers’ own accounts of their experiences of healthcare including health communication, and midwives experiences of providing care and health related information to Chinese migrant mothers. This in-depth qualitative study is based on semi-structured interviews with mothers and midwives as well as ethnographic observations of midwife appointments in Leeds and Manchester. It aims to explore how mothers’ socio-cultural values intersect with the dominant set of ideas and practices of managing pregnancy, birth and neonatal care in the British society often manifested in the ‘intensive motherhood’ discourse. More specifically it investigates what dominant (e.g. regular exercise during pregnancy; breastfeeding) and alternative health messages (birth choices) are available to Chinese migrant mothers, how mothers (dis)engage with these messages based on their material and socio-cultural underpinnings, what are the sources of information, how they evaluate the provision of health information and what are the potential areas of improvement in the maternal service.

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

Twitting rare diseases on and off the "Jolie effect": A study of twitter affordances for health public debate 30 Nov 2015

This project investigates Twitter use to discuss and build knowledge around rare diseases. It explores the impact of Twitter debate – alone and in combination with mainstream media exposure – on rare disease public discourse. It builds a comparative study of microblogging around two rare conditions that have received different mainstream media exposure: BRCA mutation – the genetic condition brought to the fore by Angelina Jolie’s New York Times op-eds on her decision to undergo preventive surgery – and Lynch Syndrome. BRCA mutation and Lynch Syndrome are comparable as they are rare genetic conditions that increase cancer risk, and their impact on life quality and expectancy may be minimised with preventive surgery. This project aims to show the ways and the extent to which Twitter debate can 1) ease public reasoning on and understanding of rare and/or uncommunicable diseases; 2) facilitate interactions among publics differently engaged in health discourse and 3) intertwine with health discussion that suddenly becomes of news value in mainstream media coverage (like in the BRCA mutation case). Results from this work have the potential to develop a research strand focused on the affordance of Twitter use for patients and lay people to impact public opinion dynamics.

Amount: £4,690
Funder: The Wellcome Trust
Recipient: University of Leicester

Mechanisms of cannabinoid modulation of dopamine release in rat brain slices in vitro 01 Apr 2016

Evidence suggests that cannabis, a widely used illicit drug in the UK, brings an increased risk of individuals developing schizophrenia in the future. Cannabinoids, the active chemicals in cannabis, may mediate this effect by modulating function in neurones of the mesolimbic dopamine pathway, although it is unlikely that this is by a direct effect on dopamine neurones themselves, since there is little evidence for cannabinoid receptors on these neurones. Rather the effects are probably mediated via glutamatergic and GABAergic neurones: in particular in the nucleus accumbens (NAc), cannabinoids may reduce GABAergic inhibition of dopamine release from the terminals. The project will use fast-scan cyclic voltammetry to measure stimulated dopamine release from NAc in rat brain slices in vitro, with an expectation that the cannabinoid (CB1) receptor agonist, ACPA, will increase dopamine release, an action which will be blocked by the GABA antagonist, picrotoxin. Given the suggested link between cannabinoids and schizophrenia, we also expect that pre-treating animals with phencyclidine (a robust animal model for schizophrenia), will disrupt ACPA modulation of dopamine release. In this way we aim to achieve a better understanding of the interaction between cannabinoids and dopamine, particularly in the context of changes occurring in schizophrenia.

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

The 1958 Birth Cohort Biomedical Resource - Facilitating access to data and samples and enhancing future utility. (bridge funding). 20 Jul 2015

This infrastructural project is targeted at strategic development of that component of the 1958 Birth Cohort(1958BC) that is known as the "Biomedical Resource". It will ensure that optimum utility can be extractedfrom the Resource during 2011-2014 and that the 1958BC will then be well placed to maintain and extend itsinternationally hailed contribution to research in the biomedical and social sciences. The proposal subsumesthree complementary objectives: (1) secure the basic infrastructure as it now exists, thus ensuring that thesuccessful systems that have already been implemented can be maintained into the future; (2) enhance theinfrastructure from an administrative and strategic management perspective to ensure that it can faceexpected and unexpected future challenges and opportunities both effectively and resiliently; (3) enhance theinfrastructure from a scientific perspective to ensure that both the 1958BC, and UK Bioscience, are bestplaced to face the scientific challenges of the future. The new science underpinning this application isfocused entirely on optimising and enhancing the utility of the pre-existing Biomedical Resource – theproposal contains no hypothesis-driven research and no funding is sought for additional data or samplecollection from study participants. The responsibility for strategic development of the cohort as a whole –including planning for future data sweeps - will remain with the Centre for Longitudinal Studies (CLS). Thisapplication reflects a considered evolution in the thinking of the funders (MRC, WT, ESRC) about strategicdevelopment of the 1958BC Biomedical Resource and of the systems and policies governing access to it.Initially, responsibility for access and strategic development lay with the Principal Investigators of theoriginal grant. But, it later became clear that if resource utility was to be optimised it should be managed anddeveloped by independent scientists and administrators. In 2008, responsibility for managing the 1958BCbiobank therefore transferred to ALSPAC laboratories at the University of Bristol under a joint grant fromMRC/WT. Then, in 2009, responsibility for oversight and strategic development of the Biomedical Resourceas a whole passed to the independent access committee chaired from the University of Leicester underanother small grant from MRC/WT. Following strategic discussions with MRC, WT and ESRC, theUniversity of Leicester and University of Bristol now outline a vision for joint management of the BiomedicalResource, to include its strategic development as an infrastructure, under a grant requesting limited - butadequate - funding to ensure sustainability.

Amount: £29,938
Funder: The Wellcome Trust
Recipient: University of Leicester