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Results

Pre- and postsynaptic determinants of neurotransmitter release at individual release sites. 30 Apr 2015

Connections between neurons are made up of several individual release sites, each with a different probability of releasing neurotransmitter upon arrival of an action potential. How pre- and postsynaptic neuron work in concert to regulate release probability (Pr) at different connection points is still unclear. A novel combination of techniques will be used to study Pr at individual active zones and to identify the mechanisms involved in its regulation. We will test the hypothesis that Pr is reg ulated in concert by both pre- and postsynaptic compartments using electrophysiology, live fluorescence imaging and serial electron microscopy both at cortical boutons and at the Calyx of Held, a giant synapse in the auditory pathway. By labelling pre- or postsynaptic cortical neurons, we will ascertain whether the presynaptic origin as well as the target neuron play a key role in setting Pr at the cellular and network-level. To reduce confounding elements, such as compartmentalised postsynaptic activity, we will use the Calyx of Held, where hundreds of active zones contact the same postsynaptic soma. This project will identify the mechanisms by which individual terminals embedded in a network set synaptic strength; with impact on detection of synaptic changes and degeneration at an early stage.

Amount: £99,715
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 publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £32,200
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

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

A new approach to the treatment of invasive pneumococcal diseases 16 Jul 2012

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: £437,952
Funder: The Wellcome Trust
Recipient: University of Leicester

An Anaerobic Crystallisation Facility at the University of Leicester. 09 Mar 2011

We propose to establish a new facility for anaerobic protein crystallisation and single crystal micro-spectrophotometry at Leicester. This facility will be critical to developing new research strategies to enable us to explore protein mechanisms within three major biological areas of interest at Leicester (many of which are WT funded): (i) Regulation of gene expression (ii) Redox enzymology of important iron-dependent enzymes (iii) Key enzymes of pathogenic microorganisms. This integrated, multi disciplinary facility will be a significant advance; it will have multiple users within Leicester and will be made available to others, since such facilities are not accessible elsewhere. The technical expertise that is needed to support this new facility is already available on-site and the new facility will form part of the on-going, long-term investment in structural biology at Leicester.

Amount: £107,562
Funder: The Wellcome Trust
Recipient: University of Leicester

Harnessing the Power of the Criminal Corpse. 09 Mar 2011

This programme brings together six interdisciplinary research strands overseen by four senior scholars with proven track records that will together produce a core history of the use and power of the criminal corpse between the late seventeenth and the mid-nineteenth centuries. The criminal corpse featured prominently in popular culture, as well as science, civic life, and medico-legal productions, and its power was harnessed for the purposes of negotiating social relationships of class, the powe r of medical men and the judiciary, and in the creation of popular and scientific medicine. Such bodies were historically significant sites of overlapping, competing, and often contradictory, understandings of human anatomy, criminal justice, popular medicine, and the social geography of the body. A broad interdisciplinary study of the use, meanings and power of the criminal corpse in Britain can be used as a vehicle for methodological and substantive advances in approaches to the wider history of the body. Additional context comes from studies of the criminal corpse in the popular imagination and its role in the development of normative ethics. An ambitious list of academic and popular outputs, including books articles and an online exhibition, ensures value for money.

Amount: £945,389
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

Seeding Drug Discovery: projects we've funded Therapeutics Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability assoc 06 Jun 2011

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: £1,029,222
Funder: The Wellcome Trust
Recipient: University of Leicester

The effects of ionising radiation on copy number variation in the mouse germline. 22 Apr 2010

The proposed research aims to evaluate, for the first time, the genome-wide effects of irradiation on the incidence of copy number variation (CNV) and other mutations in the first-generation offspring of irradiated male mice. Using microarray-based comparative genomic hybridisation, we will analyse DNA samples taken from the offspring of control and irradiated (3 Gy of acute X-rays) parents. The structure of de novo CNV rearrangements verified by qPCR will further be interrogated by sequencing o f long-range PCR products encompassing the breakpoints of the rearrangements. This work will allow us to establish the relative contribution of different mechanisms for spontaneous and radiation-induced rearrangements. Further characterisation of the full spectrum of radiation-induced mutations will be performed by whole-genome sequencing of a small subset of the offspring of irradiated parents. To investigate the effects of de novo genomic rearrangements on the expression of genes, RNA samples will be extracted from the offspring and hybridised to expression arrays. It is expected that the results of this study will provide fundamental quantitative information on the effects of exposure to ionising radiation on mutation induction in mice and will be important in improving the accuracy of the estimates of genetic hazards of ionising radiation for humans.

Amount: £431,886
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

Institutional Strategic Support Fund 2011/12. 17 Oct 2011

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

Advanced Spectrophotometric Facility. 28 Apr 2009

Ultra-violet and visible absorption/emission spectroscopy provides a powerful approach to study macromolecular interactions because of the excellent sensitivity and time resolution. The equipment requested in this application will serve a group of scientists working on diverse topics, but with a common theme of monitoring interactions between proteins, nucleic acids and small ligands in real time. These data will provide direct information about equilibrium and rate constants, and indirect infor mation about structure which will complement other techniques widely used in Leicester (e.g. X-ray crystallography and nmr). Topics under investigation include; actomyosin and associated regulatory proteins, green fluorescent protein and its variants, heme proteins and their redox partners, complement activation and lectin interactions, RNA splicing mechanisms, magnetic nanoparticles, casein kinases and GPCR phosphorylation. The modular fluorimeter is requested for high sensitivity, dual emissio n detection with a lifetime option that will be used primarily for resonance energy transfer measurements. A spectrophotometer with low stray light is required for quantifying the high absorbance of concentrated protein solutions and blocking filters. Upgrades to existing rapid-reaction equipment will ensure data can be saved in a common format for long-term storage and allow measurements with reduced dead-time.

Amount: £149,700
Funder: The Wellcome Trust
Recipient: University of Leicester

Open access award. 22 Sep 2009

Not available

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

The Molecular Functioning of HDAC:co-repressor complexes. 26 Nov 2012

Histone deacetylases (HDACs) are increasingly recognised as important targets for the treatment of cancer and other diseases including Alzheimer's. They are essential enzymes required for human development & homeostasis. HDACs 1-3 serve as the catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes function by removing acetyl groups from histones resulting in condensation of chromatin and gen e silencing. Our research is concerned with elucidating the fundamental mechanisms through which HDACs 1-3 are regulated and how they target chromatin. Our recent structure of the HDAC3 co-repressor complex identified the small signalling molecule inositol tetraphosphate (IP4) as an essential co-factor (Nature 2012, 481, 335). The breakthrough realisation that IP4 acts as an epigenetic regulator suggests a completely new and unexpected mechanism for the regulation of gene repression. More rece ntly still, we have determined the structure of HDAC1 bound to the Metastases Associated Protein co-repressor (unpublished). This structure not only reveals the basis for the specific assembly of HDACs into their cognate complexes, but also reveals how the complex is targeted to chromatin. We propose to address the major outstanding questions concerning the biological role and mechanisms of action of histone deacetylase complexes: (i) to determine the structures of the four HDAC1 and HDAC3 hol o-complexes, defining the specificity of assembly and their role in determining target gene and substrate specificity (ii) to understand the biological role of IP4 in regulating HDAC complexes (iii) to explore potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides

Amount: £2,391,777
Funder: The Wellcome Trust
Recipient: University of Leicester

The role of PML in the nervous system and in the pathogenesis of neuroblastoma. 06 Jun 2009

We have found that expression of the tumour suppressor PML is frequently lost in both mouse and human neuroblastoma primary tumours. We have also shown that PML acts as a growth suppressor at the level of neural progenitor/stem cells during embryonic development. This suggests that PML loss could be instrumental in leading to uncontrolled proliferation and a block of maturation in neuroblasts. Our key goal is to determine the involvement of PML in the pathogenesis of neuroblastoma. To this end, we set the following objectives: i) to assess whether the loss of PML expression correlates with disease outcome; ii) to determine the effect of PML loss on tumour growth in a mouse model of neuroblastoma; iii) to understand the molecular mechanisms underlying the loss of PML expression in neuroblastoma; iv) to establish the effects of PML re-expression in explants from mouse tumours and derived cell lines.

Amount: £156,828
Funder: The Wellcome Trust
Recipient: University of Leicester

CAPP Ceramide Activated Protein Phosphatase in yeast. 28 Apr 2009

In eukaryotes, excess levels of the sphingolipid ceramide can block cell proliferation. This proposal aims to provide further insights into ceramide toxicity by studying a ceramide-activated protein phosphatase (CAPP) complex that is hardly understood. Using the yeast Saccharomyces cerevisiae as a model system, we will identify the sphingoid signal required for CAPP activity and elucidate the subunit composition of the CAPP complex. The latter will involve immuneprecipitation and multi-copy comp etition studies to identify the regulatory subunits that in concert with the Sit4 phosphatase catalytic subunit assemble into the CAPP complex. Based on our previously published observations that a subunit of the Elongator complex is a Sit4-dependent phosphoprotein and required for ceramide toxicity, we will study whether CAPP targets Elongator as a ceramide-dependent substrate. A more comprehensive substrate spectrum of CAPP will be obtained by identifying a kinase suppressor of ceramide which will be screened for ceramide resistance in a kinome-wide fashion overexpressing yeast protein kinases. Eventually, we anticipate that our proposal will provide a much clearer picture of how dephosphorylation by CAPP is involved in ceramide signalling and cell death, how CAPP activity is regulated by sphingolipids and what protein phosphorylation events CAPP may potentially cross-talk with.

Amount: £238,396
Funder: The Wellcome Trust
Recipient: University of Leicester