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

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Results

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

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

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

Rescue of secretion of disease-associated misfolded glycoproteins in UGGT1 knock-out cells 06 Sep 2018

UGGT1 is the checkpoint enzyme of the endoplasmic reticulum (ER) glycoprotein folding quality control (ERQC) machinery. Many a devastating human disease is caused by a mutation causing a slightly misfolded, but nevertheless functional protein that is flagged for ER retention by UGGT1 and ultimately degraded. The Seed Award in Science will enable me to test the hypothesis that modulation of UGGT1 can rescue the secretion of the mutant, but functional, misfolded glycoprotein, and alleviate the pathogenic consequences of the mutation. Rescue of secretion by UGGT1 deletion was tested successfully once in a plant but never in animals or mammalian cells. To do this, I will follow fluorescently tagged misfolded glycoprotein mutants in UGGT1 CRISPR/Cas9 knockout and wild-type (WT) mammalian cells. I will also use mass spectrometry to compare UGGT1 knockout cells to WT cells, to determine what impact UGGT1 deletion has on the overall secretome. These experiments if successful will make the case for the development of ERQC small-molecule modulators and the establishment of a personalised medicine strategy for the therapy of glycoprotein misfolding congenital syndromes. Unlike mutant-specific pharmacological chaperone therapies, hitting UGGT1, the one and only ERQC checkpoint, would benefit patients suffering from a broad range of rare disease.

Amount: £99,509
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

Exploiting transcription of repetitive DNA to study early events in colorectal cancer 25 Apr 2018

Molecular changes occurring before cancer can be detected by commonly used methods provide potential biomarkers for early detection if routine screening were in place. To date, research has focused mainly on unique DNA largely disregarding the 55% composed of repetitive sequences like LINE-1s. LINE-1s are usually silenced in normal tissues but active in cancer and are best known for their ability to move to other locations in the genome with obvious deleterious implications. Mobilisation first requires activation of LINE-1’s promoters, but, intriguingly, those of both mobile and immobile LINE-1s become active in cancer. To fully understand the functional consequences of this transcriptional activity requires overcoming the challenges of studying individual LINE-1s. Using innovative approaches, we identified a LINE-1 whose activation is linked to silencing of a tumour suppressor gene and whose product can be detected in the blood of colorectal cancer patients. I will build on this knowledge to determine to determine why and which LINE-1’s promoters are active in colorectal cancer and what are the effects of this activation on neighbouring genes. I will examine in liquid biopsies the biomarker potential of the novel, aberrantly expressed genes so identified, with a long-term aim to help refine current tests.

Amount: £455,076
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

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

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

Mutation and diversity in copy number variable genes. 25 Feb 2009

The research will develop methods pioneered in the department to precisely analyse sequence variation between different copy number haplotypes of the FCGR3 gene, and to infer recurrent ectopic recombination breakpoints between the FCGR3A and FCGR3B repeats. This information will inform assays designed to assess the frequency of de novo deletion and the amount of somatic copy number variation at this locus. Key goals are: 1. A sequence-level catalogue of coding and non-coding sequence variatio n of the FCGR3A and FCGR3B repeat haplotypes using genome fractionation by pulsed-field gel electrophoresis followed by high-throughput sequencing, distinguishing differences between paralogues from allelic differences. 2. Identification of historical ectopic recombination breakpoints in 45 deletion copy number haplotypes from this sequence catalogue. 3. Development of an assay to specifically amplify de novo deletion haplotypes from genomic DNA. 4. Use this assay to determine frequency of d e novo deletion in sperm.

Amount: £338,747
Funder: The Wellcome Trust
Recipient: University of Leicester

CRACM ion channel function in human lung mast cells. 11 Feb 2009

We hypothesise that CRACM ion channels contribute to the Ca2+ influx pathway in human lung mast cells (HLMC) and may therefore serve as novel targets for the treatment of asthma and related diseases. We wish to strengthen this hypothesis by defining: 1. The mRNA and protein expression of CRACM channels in HLMC using quantitative RT-PCR, western blotting and flow cytometry, and their functional expression examined on single cells using patch clamp electrophysiology. 2. The functional role of CRACM channels in mast cell Ca2+ influx, secretion, migration, proliferation, survival and adhesion as determined by both pharmacological blockade and knock-down experiments using RNA interference and by overexpression of dominant negative pore mutants. 3. The factors regulating the gene expression and trafficking of CRACM channels to the mast cell plasma membrane determined by real-time PCR and live cell confocal microscopy. 4. The ability of CRACM channels to form signalling complexes with the Ca2+-activated K+ channel KCa3.1 and 2-adrenoceptor, determined by pharmacological manipulation, over-expression of epitope-tagged native and mutant channels, shRNA knockdown, and co-immunoprecipitation. 5. The effects of CRACM blockade on cell activation within cultured bronchial tissue explants. These studies will significantly enhance our understanding of the electrical mechanisms controlling HLMC function.

Amount: £272,360
Funder: The Wellcome Trust
Recipient: University of Leicester

Characterizing SUN protein interactions at the nuclear envelope and their role in Emery-Dreifuss muscular dystrophy. 25 Feb 2009

Nuclear-cytoskeletal attachments are proposed to provide mechanical strength to cells through direct structural connections extending from the plasma membrane to nucleoskeleton. We and others have demonstrated that the inner nuclear membrane proteins, SUN1 and SUN2, link the nucleoskeleton and cytoskeleton via interactions with giant nesprin isoforms located in the outer nuclear membrane., We have recently shown that SUN1/2 also interact with lamin A, emerin and short nesprin isoforms at the inn er nuclear membrane. Mutations in lamin A/C, emerin and nesprin 1/2 are associated with the muscle-wasting disorder Emery-Dreifuss muscular dystrophy (EDMD). Furthermore, we now have preliminary evidence of SUN1 mutations in EDMD patients. We therefore propose that SUN1/2, lamin A, emerin and nesprins form a complex that is essential for muscle cell integrity due to their constant exposure to mechanical stress. We will use our combined expertise in cell biology and molecular genetics to examine the role of SUN proteins in EDMD using three approaches: i) delineation of the respective protein binding sites and their interdependence; ii) comprehensive identification of SUN1 and SUN2 gene mutations in EDMD patients and, iii) functional analysis of SUN-disrupted and EDMD cells for defects in NE protein expression and localization, cell migration and mechanical strength.

Amount: £349,243
Funder: The Wellcome Trust
Recipient: University of Leicester

Autotransported proteins of Burkholderia pseudomallei. 02 Oct 2008

The autotransporters, a family of secreted or membrane anchored proteins from Gram-negative bacteria, are released from the bacteria through a pathway termed type V or autotransporter secretion. Many members of this family have been implicated as important or putative virulence factors in various bacterial pathogens. Each pathogen has an unique set of atotransported proteins, however there is a significant sequence conservation in some parts of such proteins among various species, so genes of pu tative autotransporters can be identified in the available genomic sequences. Following this, the autotransporter-encoding genes can be mutated, and phenotypes associated with such mutations could be assessed. The virulence-associated proteins could be identified and characterised. Such research will undoubtedly contribute to the understanding of molecular mechanisms underlying bacterial pathogenicity and may aid the discovery of new targets for antimicrobial and vaccine development. Here, we p ropose to analyse the repertoire and functions of the autotransported proteins from B. pseudomallei and to assess their role(s) in the bacterial-host cell interactions and virulence. Defined mutants in all autotransported-encoding genes will be created and analysed in vitro and in vivo. The biochemical functions of selected autotransporters will be investigated. This study will provide valuable insights into the B. pseudomallei virulence mechanisms.

Amount: £280,818
Funder: The Wellcome Trust
Recipient: University of Leicester

A new approach to the treatment of invasive pneumococcal diseases 31 Aug 2009

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: £502,026
Funder: The Wellcome Trust
Recipient: University of Leicester