- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
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 14 Jul 2014
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.
The 1958 Birth Cohort Biomedical Resource - Facilitating access to data and samples and enhancing future utility. 20 Oct 2010
The 1958 Birth Cohort (1958BC) recruited 17,416 British newborns 3-9 March 1958. A BiomedicalResource (58BMR) was later created by the biomedical survey (Strachan, Power, Bynner[2002/3]) to include extensive questionnaire data, physical measures and biosamples on 1958BCparticipants. The biosamples, stored in ALSPAC laboratories at the University of Bristol, includeblood, urine and saliva (9,000+ participants), DNA (8000+), lymphoblastic cell lines (7,500+). Mostparticipants providing DNA have been genome-wide-genotyped (data held at European-Genome-Phenome-Archive). Other data are held at UK-Data-Archive, managed by Centre for LongitudinalStudies. The 58BMR is used widely by biomedical, social and population scientists nationally andworldwide. 58FORWARDS will maintain and develop the infrastructure for managing, linking andreleasing biosamples/data from 58BMR, facilitating scientific exploitation by makingbiosamples/data readily available for sharing. 58FORWARDS has three aims: (1) Fund andsupport pre-existing procedures and systems that have underpinned the 58BMR for >10 years; (2)Ensure targeted development of key systems and procedures to meet rapid, and understandable,changes in the strategy of national funders regarding infrastructural support for major UK cohorts;(3) Ensure that access to data and biosamples from the 58BMR remains streamlined and securethrough all maintenance and development work.
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.
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.
The majority of the malignant tumours contain mutations in p53 resulting in the expression of a mutant p53 protein. This protein has not only lost its transcriptional tumour suppressive functions, but has also gained novel functions in driving metastasis and developing resistance to chemotherapy. To a certain extent these novel functions comprise mutant p53s ability to inhibit other transcription factors, including p63. The overall aim of my research program is to better understand the processes underlying mutant p53 gain-of-function in invasion and chemo-resistance. The key goals of my proposed research are: (1) To further characterise the inhibitory role of mutant p53 on p63. (2) To explore the role of mutant p53 in the regulation of Dicer (a target gene of p63) and microRNA biosynthesis. (3) To characterise the role of mutant p53 (and loss of p63) in chemo-resistance and to demonstrate a role for multidrug receptor recycling in chemo-resistance. (4) To assess the role of the mic roenvironment in the behaviour of mutant p53 cells to chemo-therapy.
This research project, which informs a new monograph I am writing for Rutgers University Press, entitled 'Voices of Health and Illness: Medicine, Psychiatry, and American Culture, 1970-2000', examines mental health care reform during five modern United States presidencies: those of Bill Clinton (1993-2000), Ronald Reagan (1981-89), Jimmy Carter (1977-81), Gerald Ford (1974-77) and Richard Nixon (1969-74). The substantial body of healthcare reform papers housed in these five presidential librari es will provide the historical spine for my monograph, which traces and analyses the development of mental health provision during the last thirty years of the twentieth century. While Presidents Carter and Clinton, and particularly the First Ladies, Rosalynn Carter and Hillary Clinton, were very serious about healthcare, I will contrast these two Democratic administrations with more piecemeal reforms during three Republican administrations, focusing on Nixon's and Ford's attempts to redress the cost of President Johnson's landmark healthcare legislation and Reagan's move away from Carter's Mental Health Systems Act of 1980. My project will assess to what extent this Act - the product of Carter's Presidential Commission on Mental Health (1977-78) - was revived by the Clinton administration in the late 1990s, when mental health care surfaced once again as a priority.
The role of mast cell and airway smooth muscle interactions in the pathophysiology of asthma. 31 May 2012
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 interms 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 mastcells from lung resection material.
Medicine, computus and quadrivium in English manuscripts of the 11th and early12th centuries. 16 Apr 2012
This project forms part of a larger study of scientific and medical learning in England in the 11th and 12th centuries, focussing on the nexus between change in the mathematical sciences (quadrivium) and computus (time-reckoning), and change in medical science. In the 200 years straddling the Norman Conquest and the reception of Greco-Arabic learning, England was actively participating in new trends in both domains. Recent scholarship on medicine has confirmed England's openness to Salerno's "theoretical turn", but has neglected medical materials lodged in quadrivium/computus manuscripts, especially those written after 1100. My hypothesis is that reception of new medicine cannot be detached from reception of other kinds of scientific learning which share the same manuscript context. Two manuscripts written shortly around 1100, Durham Hunter 100 and Oxford St John's College 17, contain a distinctive mix of both old and new materials about both medicine and quadrivium/computus. This project aims to analyse the sources of their medical texts, and compare them to contemporary English manuscripts of similar character, in order to situate medical learning in a process of intellectual and cultural transition. It will result in an article, which will be expanded into a chapter in the projected monograph.
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.