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Results

Open Access Awards 2017/18 30 Sep 2018

Not available

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

Pelvic floor disorders in women in rural Ethiopia 21 May 2018

Urinary incontinence (UI) and pelvic organ prolapse (POP) commonly affect women after childbirth. In the developed world initial treatment is non-surgical with pelvic floor exercises for UI and vaginal support pessaries or pelvic floor exercises for POP. Working with colleagues in Ethiopia we know that UI and POP affect much younger women, with greater severity. Conservative treatments are not offered because of lack of trained personnel, and significant difficulties with transport and access to care. Pelvic floor disorders are a modern epidemic and the introduction of sustainable treatment models is a public health priority. Our longterm goal is to design acceptable, sustainable and deliverable fully developed conservative treatment interventions for the treatment of pelvic organ prolapse and urinary incontinence to be disseminated, delivered and evaluated in a large prospective study. This application will fund three workpackages which bring key disciplinary perspectives together to lay the groundwork for this goal: a priority setting partnership in Gondar, Ethiopia; formative research with qualitative interviews to understand views and experiences of women and stakeholders to inform the design of the intervention, and an exploration of individual and community stigma associated with the condition to develop educational materials using concepts of communication for social change.

Amount: £99,864
Funder: The Wellcome Trust
Recipient: University of Leicester

What limits visual acuity in patients with infantile nystagmus? 31 May 2018

We hypothesize that the visual acuity is limited in patients with infantile nystagmus due to the arrested retinal development and nystagmus characteristics. The main research question is to investigate the combined effects of retinal development and nystagmus characteristics on the visual acuity of patients with infantile nystagmus. Specifically we will quantify retinal development by grading optical coherence tomograms using a foveal hypoplasia grading system developed at Leicester. Additionally, we will segment the intra-retinal layers at the fovea to derive thicknesses measurements including the cone outer segment thickness which is a surrogate marker for cone photoreceptor spacing. Nystagmus characteristics such as intensity, eye velocity and eXpanded Nystagmus Acuity Function (NAFX) will be calculated from eye movement recordings. A mixed model will be used to determine the level of contribution of each of these factors to the visual acuity of patients with infantile nystagmus. Understanding the contributory factors to reduced visual acuity in nystagmus will help determine therapeutic strategies to improve vision and provide prognosis for patients.

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

Identification of novel HDAC1 ‘proximate’ proteins and substrates using APEX2 31 May 2018

Histone deacetylase 1 (HDAC1) has been implicated in almost all cellular process from cell cycle, DNA synthesis, DNA repair to gene expression. However, the key interactions required for these activities remain poorly defined because studies have largely been performed by large-scale co-IPs (which may not identify weak or transient associations) in asynchronous and untreated cells. Novel methodologies have been developed which monitor the proximity of protein associations using biotin ligation e.g. Bio-ID. This has the advantage of using intact cells, requires no cross-linking and allows the identification of both binding partners and transiently associated proteins such as substrates. In this application we intend to contribute to the identification of novel HDAC1 associated proteins and substrates using a novel ‘APEX2’ biotin-ligation approach. The power of the APEX2 approach lies in its 1-minute labelling time. This will enable us to assess HDAC1 proximate proteins during different phases of cell cycle (e.g. G1/S/G2/M) and +/- DNA damaging agents (e.g. Doxorubicin, UV-light). These experiments should provide a comprehensive view of HDAC1 associated proteins at an unprecedented level of precision in terms of cell cycle and response to signalling pathways.

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

Metabotropic glutamate receptor modulation of mesolimbic dopamine release: effect of phencyclidine pretreatment modelling schizophrenia 31 May 2018

Schizophrenia is a severely debilitating mental condition, affecting ~0.5% of the population. Current theories suggest a core deficit in cortical glutamate which causes dysregulation of glutamatergic control of dopamine release in nucleus accumbens. In particular phasic (high-frequency) activity, related to attentional processes, rather than tonic (low-frequency) activity, is vulnerable. However, remarkably little is known about mechanisms involved. Phencyclidine (glutamate antagonist), causes changes in people, resembling schizophrenia. In animals, short-term chronic treatment causes behavioural deficits mimicking changes in schizophrenia, providing an animal model for studying causative mechanisms. In clinical trials, type-2 metabotropic glutamate receptors (mGluR2) agonists alleviated psychotic symptoms. In rats they reverse psychomimetic effects of phencyclidine and modulate accumbal dopamine release. We suggest that these processes are dysfunctional in schizophrenia, which accounts, at least in part, for glutamate-dopamine dysregulation. The aim of this study is to use fast cyclic voltammetry in vitro, to characterise the effects of activation of mGluR2 on stimulated accumbal dopamine release, particularly focussing on differences between phasic and tonic stimuli, and assess whether this modulation is disrupted by subchronic phencyclidine pretreatment, modelling schizophrenia. Identifying fundamental mechanism determining glutamatergic modulation of accumbal dopamine function, and dysfunction in model schizophrenia, underpins further research developing novel antipsychotic treatment strategies.

Amount: £0
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

A new approach to the treatment of invasive pneumococcal diseases 16 Sep 2013

Streptococcus pneumoniae causes a very high number of cases of pneumonia, meningitis and bacteraemia, worldwide. Despite using antibiotics that kill the bacterium, a large number of patients still die and in meningitis, many survivors have profound neurological handicap. This is because the bacterium produces a very damaging virulence factor that is not inhibited by antibiotics. This problem constitutes an unmet medical need that Professor Peter Andrew and colleagues from the University of Leicester are proposing to fulfill. They have identified that small molecules can inhibit this virulence factor and are effective in vivo. The team have been awarded funding through the Seeding Drug Discovery initiative to identify new small molecules and through a programme of medicinal chemistry, combined with in vitro and in vivo testing, to identify lead compounds with appropriate efficacy, pharmacokinetics and toxicology. The aim is that giving such molecules will reduce the number of patients that die or suffer handicap as a result.

Amount: £196,000
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

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £38,204
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

Social media and adolescent mental health: A preliminary qualitative exploration of the potential use of social media for promoting mental health and wellbeing among 12-18 year olds. 20 Jul 2015

The World Health Organization recognised that there is no health without mental health (WHO, 2005). Despite this, research from many countries has demonstrated that there is a high level of unmet need for mental health (Schomerous & Angermeyer, 2008). This is particularly concerning for children and adolescents. It is well-known that mental health problems increase during mid-to-late adolescence (Burns et al., 2009). While it remains unclear why young people are reluctant to seek help, barriers have included stigma, trust of professionals, and concerns about the characteristics of the provider (Gulliver et al., 2010). In a contemporary digital society it is arguable that social media may be a way of providing information to adolescents and to promote help-seeking behaviour. However, despite the potential, research is only just starting to grapple with the possibilities. It is therefore important that we have a greater understanding of this by exploring adolescents views and engaging me ntal health professionals in the debate. By consulting with these two groups though focus groups and interviews we can gain a better understanding of how adolescents use social media and provide an analysis of the potential benefits and limitations for social media as a mental health promotion tool.

Amount: £4,160
Funder: The Wellcome Trust
Recipient: University of Leicester

Institutional Strategic Support Fund FY2013/14 14 Oct 2013

Neuroscience & Behaviour Leicester has clear strengths in neuroscience and behaviour research and our previous ISSF encouraged new appointments and substantial grant funding Genomes and ‘Big Data’ Genome variation and dynamics is a long-standing cornerstone of research excellence at Leicester. Stratified Medicine. Modern genomic and biomarker studies are revealing heterogeneity in susceptibility, prognosis and treatment responses of patients assigned to established diagnostic groups. Our previous ISSF award allowed us to invest in next generation sequencing and proteomic infrastructure to interrogate this heterogeneity Public Health Our Population Science and Diabetes research themes are central to Leicester’s contribution in bridging the second translational gap, converting preclinical and clinical research into public health outcomes. (ii) Facilitation of collaborative initiativesLeicester’s biomedical research strategy is driven through our College research themes. However, all themes have affiliates from other Colleges, with a specific Life-Sciences Interface Theme crossing our College and the College of Sciences and Engineering (iv) Public engagement strategyOur new ISSF award will allow us to develop and deliver a more focused public engagement (PE) strategy that will build upon the previous general good practice within our College. We will develop a coordinated plan via two complementary mechanisms

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Leicester

Open access award 2012/13. 17 Sep 2012

Not available

Amount: £90,000
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

NIMA-related kinases in cell cycle control and human disease. 10 Jul 2007

NIMA, a serine/threonine kinase, was identified in a genetic screen as an essential regulator of mitotic entry in Aspergillus nidulans. Like other important cell cycle regulators, NIMA-related kinases are conserved across all eukaryotes. The human genome encodes eleven NIMA-related kinases (Nek1-Nek11) that form a distinct family representing about 2% of the entire kinome. We have established an international track record in studying the regulation and function of Nek2, the most closely related sequence to NIMA, demonstrating that it is a cell cycle-dependent kinase that localizes to the centrosome, regulates spindle formation upon mitotic entry and is overexpressed in human cancer. Much less is known about the other human Neks although evidence is emerging from our group and others that Nek6, Nek7 and Nek9 also regulate mitosis. Surprisingly, Nek1 and Nek8 are mutated in mouse models of polycystic kidney disease (PKD), a disease that frequently results from ciliary defects. Hence, an underlying theme for Nek kinase function may be in coordinating cell proliferation and ciliogenesis through microtubule regulation. The aim of this programme of research is to test this hypothesis by undertaking a comprehensive analysis of the regulation and function of human Neks in dividing and differentiated cells.

Amount: £992,664
Funder: The Wellcome Trust
Recipient: University of Leicester

Characterisation of P2X1 receptor function, regulation and development of molecular models of drug action at ATP gated P2X receptors 09 Nov 2006

ATP gated P2X1 receptor channels play important roles in the cardiovascular system contributing to the control of arterial tone as well as blood clotting and may be novel targets for the development of anti-thrombotic drugs. The aim of this proposal is to study the neuronal role, regulation and molecular properties of P2X1 receptors. (i) To address the role of P2X1 receptors in the nervous system we will generate a fluorescent P2X1-EGFP knock-in reporter mouse to identify and characterise the receptor in live cells. (ii) P2X1 receptors are expressed in lipid rafts, phosphorylated and sensitive to the intracellular environment. We will determine the extent and mechanisms of P2X1 receptor regulation by other receptors, the contribution of the intracellular domains to channel function and identify the role of interactingproteins in modulating receptor properties. (iii) We have used a mutagenesis approach to identify conserved residues in the extracellular domain that are involved in ATP action, however the pharmacological differences between subunits suggest that variant amino acids are also important in drug binding. We aim to use cysteine scanning mutagensis and analysis of the site of binding of cross-linked ATP analogues to develop molecular models of agonist and antagonist action at P2X receptors.

Amount: £1,128,406
Funder: The Wellcome Trust
Recipient: University of Leicester

Purinergic signalling in Dictyostelium discoideum. 22 Feb 2007

Extracellular nucleotides act at ionotropic P2X and metabotropic P2Y receptor families and play a fundamental role in a wide array of physiological processes including neurotransmission, smooth muscle contraction, immune cell function and platelet aggregation. We have recently identified a family of P2X-like proteins and demonstrated a purinergic calcium response in the amoeba Dictyostelium. This opens a unique opportunity to explore the molecular mechanisms governing purinergic receptor functio n in a well established model eukaryotic organism offering a range of powerful molecular genetic techniques and functional screens. In this project we aim to establish Dictyostelium as a model system for purinergic receptor research. We will characterise the functional properties of Dictyostelium P2X-like receptors by electrophysiology in Xenopus oocytes and by recording calcium responses in aequorin expressing Dictyostelium. A genome wide screen of orphan Dictyostelium GPCRs will be conducted b y RNAi to identify P2Y receptors and the molecular identity of the receptors mediating the purinergic calcium response will be determined by analysis of null and overexpressing purinoceptor strains. GFP-tagged receptors will be used to determine subcellular localisations and roles in cellular function will be investigated by studying phenotypic changes due to ablation and over expression of purinergic receptor genes.

Amount: £120,525
Funder: The Wellcome Trust
Recipient: University of Leicester

The role of mast cell and airway smooth muscle interactions in the pathophysiology of asthma. 07 Jun 2007

We hypothesise that airway hyperresponsiveness and persistent airflow obstruction in asthma result from a) intrinsic abnormalities in airway smooth muscle (ASM) from asthmatics and b) interactions between ASM-mast cells. We aim i) to examine the differences between ASM from asthmatics and non-asthmatics and to determine the mechanisms underlying these differences in terms of calcium homeostasis using single cell and FLIPR analysis; contractility using collagen gel contraction assays and single c ell measurements of maximal contraction and velocity; synthetic capacity using a variety of approaches including ELISA, immunoblotting, proteomics, qPCR and gene array; migration using 2D assays; proliferation by MTS assay and thymidine incorporation; and survival by Annexin V and PI staining, ii) to investigate in vitro the effect of ASM-mast cell interactions on ASM and mast cell function respectively and to confirm effects, as appropriate, in tissue and iii) to confirm that localisation of ac tivated mast cells in the ASM-bundle is a feature of asthma across severity of disease and to determine whether this is affected by corticosteroids or experimental viral infection. For the in vitro experiments we shall use freshly isolated and primary ASM cultures from bronchial biopsies from asthmatics and controls and primary mast cells from lung resection material.

Amount: £1,212,043
Funder: The Wellcome Trust
Recipient: University of Leicester

Investigation of the role of protein phosphorylation in the erythrocytic stage of the human malarial parasite Plasmodium falciparum. 01 Oct 2009

This project is divided into three objectives: 1. To determine the global phospho-proteome in the schizont stage of P. falciparum. 2. To establish the phosphorylation networks regulated by specific protein kinases that are essential for parasite viability. 3. To determine the role of phosphorylation in parasite growth and invasion into red blood cells. Meeting these objectives is centred on the integration of three core approaches. The first is the application of biochemical/mass spectro metry techniques that will define the phospho-proteome of P. falciparum. The second is the use of a novel chemical genetics approach in combination with pharmacological inhibitors to inhibit specific protein kinases and thereby probe the molecular mechanisms by which phosphorylation contributes to parasite viability. Thirdly, the phosphorylation events discovered in this project will be set in a functional context by studying progression of the parasite through the erythrocytic cycle and parasit e invasion into erythrocytes. By combining these three approaches we aim to both further our basic understanding of the role played by phosphorylation in P. falciparum but also to contribute to the protein kinase based drug discovery programme being conducted in the Doerig lab (co-applicant).

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Leicester