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Results

Volunteering Matters 06 Nov 2014

Piloting Engage and Transform, a scheme to break down cultural barriers and develop a long-term partnership of mutual benefit between public and social sector organisations.

The cellular mechanisms of cortical map reorganisation in primary sensory cortex. 12 Jul 2006

A large part of the neocortex is given over to topographic representations of sensory inputs and motor outputs. Many of these maps express experience-dependent plasticity in adulthood. This is of great neurological interest because cortical reorganisation probably contributes to recovery from brain damage. Harnessing experience-dependent plasticity potentially offers therapeutic benefits. However, the simple strategy of maximising plasticity will not work because excess or aberrant reorganisation may cause disease. Realising any therapeutic gain will, therefore, require an understanding of the cellular mechanisms that drive cortical map reorganisation. The sensory input from rat whiskers to primary somatosensory cortex provides an ideal model system to study cortical map plasticity because brief periods of whisker trimming results in reorganisation of the corresponding cortical map. I will investigate the underlying cellular mechanisms level by preparing in vitro brain slices of primary somatosensory cortex that cut across the whisker barrel rows. My general strategy will be to patch clamp paired neurons in the supragranular cortex and to characterise the electrophysiology and the neuroanatomy of the connection between the neurons. Short-term synaptic dynamics will be used as a probe to assess the strength of single-axon connections. The neurons will be filled with biocytin. Triple-label immunofluorescence combined with confocal microscopy will detect biocytin filled neurons, presynaptic boutons and postsynaptic density. Colocalisation of the three labels indicates the site of synapses between the two neurons under study. I will define how the short-term dynamics of excitatory intracortical synapses vary with the period of deprivation and assess whether synaptic number changes contemporaneously. A parallel study will focus on the synaptic dynamics of inhibitory circuitry in supragranular cortex. This will determine whether inhibition is affected by sensory deprivation and help to assess if the balance of excitation and inhibition is altered. Finally, a complementary series of experiments will test the hypotheses that long-term potentiation/depression drive the alterations in synaptic dynamics found at the junction of deprived and spared cortex.

Amount: £400,414
Funder: The Wellcome Trust
Recipient: King's College London

Cognitive and social processes in psychosis: developing more effective teatment approaches. 23 Jan 2006

The aim of our research is to advance the understanding of psychosis, in order to improve treatment. Schizophrenia-spectrum psychoses are distressing and disabling for sufferers, place high demands on carers and have high health and social care costs. The effectiveness of medication, the first line treatment, is limited and the risk of relapse is high. Our research strategy is to combine two major outcome trials of psychological treatments with a linked series of explanatory studies. We have developed and evaluated two treatments, cognitive behaviour therapy (CBT) and family interventions (FI). Both are known to be effective, but they have different targets of change and little is known about how they work. Our model of psychosis identifies specific cognitive and social processes which we hypothesise to maintain psychosis and to be important targets of treatment. We intend to test this model to improve understanding of change processes and enhance treatment effectiveness. After five years, we aim to have confirmed that CBT reduces relapse; to have identified processes which maintain psychosis and contribute to relapse; to have identified how CBT and FI work; and to have refined both treatments to meet specific clinical needs.

Amount: £55,000
Funder: The Wellcome Trust
Recipient: King's College London

MA in Medicine, Occupation and Health in Historical Perspective. 30 Aug 2006

University of Exeter: Master's Degree in the History of Medicine Course title: MA in Medicine, Occupation and Health in Historical Perspectives. This MA is the multi-disciplinary study of the role of modern medicine in the workplace in an international context. It integrates the history of medicine and medical practice with contemporary issues in occupational health. The one year programme is structured in the following way: (a) Historical Skills and Methodology, (b) A core course consisting of two specialist modules in the history of medicine and issues in occupational health. The optional modules include, but not limited to: Medicine and Social Policy in Modern Britain; Population; Disease and Health in Modern Britain; Sociology of Reproduction; The Sociology of Science and Technology; Nineteenth Century Science and Gender. (b) Fieldwork: Students may develop an individual fieldwork module in collaboration with staff. This will enable a student to combine professional and/or personal experience with an intellectual perspective on the historical development of their chosen area. Dissertation: individual topic of 20,000 words, agreed between individual students and the programme director. The course is delivered in Semesters 1 and 2, taken up with taught modules. The focus is on providing both a broad knowledge of issues in medical history and occupational health in the modern world and also the basic training in skills required for conducting research in medical history.

Amount: £19,823
Funder: The Wellcome Trust
Recipient: University of Exeter

Testing a cognitive model of paranoia: experimental studies using virtual reality. 13 Dec 2005

Paranoia occurs in the general population on a continuum from mild suspiciousness to delusions of persecution. Such thoughts are frequently distressing and can be a severe clinical problem. The key goal is to test rigorously the applicant's cognitive model of paranoia (Freeman et al, 2002; Freeman & Garety, 2004). This will exploit a new methodology. It has recently been shown that paranoid thoughts can occur in response to neutral Virtual Reality (VR) characters (Freeman et al, 2003; Freeman et al, in press). Paranoia in VR is associated with having similar thoughts in the real world. Unfounded persecutory ideation can therefore be studied under controlled laboratory conditions. The cognitive model will be used to predict paranoid thoughts in VR. Further, in order to test the causal role of key factors, the effect of manipulating variables on the occurrence of paranoid thoughts in VR will be investigated. Anxious ideation in VR will also be assessed to examine the additional factors associated with paranoid thoughts. Finally, the model will also be tested by examining its ability to predict paranoia after a real-life negative event (an assault) that raises levels of paranoid thoughts. Such theoretical advance can improve cognitive behavioural interventions for paranoia.

Amount: £568,079
Funder: The Wellcome Trust
Recipient: King's College London

Mechanisms by which fibroblasts from different origins modify the transendothelial recruitment of T-cells and their retention in inflammed tissue. 07 Nov 2005

Our key goal is to show how the recruitment of T-lymphocytes through vascularendothelium and subsequent retention in tissue might be modifed by stromal cells, particularly synovial fibroblasts from patients with rheumatoid arthritis. We suggest that there is a variable stromal 'postcode' whereby fibroblasts in different regions influence the development of inflammation by virtue of their patterns of gene expression, e.g., for chemokines and growth factors. This leads to the hypothesis that fibroblasts fulfill an important regulatory function which becomes modified in chronic inflammatory disorders, causing lack of control of the deposition of T-cells in tissue. We will use endothelial-fibroblast co-culture systems developed in Birmingham, to examine time courses of adhesion and migration of T-cell subsets on endothelial monolayers, and movement through sub-endothelial layers of fibroblasts. These models will incorporate delivery of T-cells from flow and stimulation with cytokines where appropriate. Fibroblasts from different sources will be compared. Based on variations in recruitment and retention ofT-cells, we will disect gene expression and production of cytokines and chemokines, to identify mediators of differential responses. We will test theroles of candidate mediators using blocking strategies. Thus, we aim to identify critical factors affecting 'resolution' of normal and disrupted inflammatory processes.

Amount: £199,177
Funder: The Wellcome Trust
Recipient: University of Birmingham

Model systems to study hepatitis C virus tropism for the liver. 25 Oct 2005

Studies on Hepatitis C virus (HCV) cell entry and tropism have largely been ignored due to technical limitations in our inability to propagate HCV in cell culture. However, the development of infectious retrovirus pseudotypes bearing HCV glycoproteins (HCVpp) has allowed studies to analyze the cellular molecules required for HCV-cell entry. More recently, we and others have shown the JFH strain of HCV is able to assemble and release infectious particles in cell culture (HCVcc). This proposal will compare the receptor usage and tropism of HCVpp and HCVcc and will aim to select the most appropriate system to study the mechanism(s) of viral entry. Our current research shows that HCVpp and HCVcc infectivity is dependent on host cell expression of CD81 and additional unidentified liver specific molecule(s). We will define the role(s) of CD81, scavenger receptor B I and associated cellular proteins in HCV attachment and internalization into primary hepatocyte and hepatoma derived cell lines. We hypothesize that liver specific molecule(s) modulate the receptor activity of CD81 and identification of CD81-protein complexes within permissive cells will elucidate the HCV-protein interactions required for virus infection. Understanding the receptor requirements for HCV entry will aid in the design of small animal models for HCV infection.

Amount: £767,361
Funder: The Wellcome Trust
Recipient: University of Birmingham

Role of Rho GTPase signalling pathways in neuronal morphogenesis. 13 Dec 2005

Cytoskeletal regulation leading to cell shape changes are crucial during cell division, motility and morphogenesis. My aim is to understand how signalling pathways regulate the cytoskeleton to elicit neuronal morphogenesis. My recent work has shown that Rho GTPases are key intracellular regulators of axon growth, guidance and branching and that different pathways are involved in these processes. Part of this proposal will build on key preliminary observations on the roles PI3K/Akt, JNK and cytoskeletal regulated pathways may play in neuronal morphogenesis. As cells require multiple signals to elicit appropriate responses, the goal is to not only characterise how distinct intracellular pathways are involved but also to elucidate how multiple pathways are integrated during morphogenesis. Numerous evidences reveal that nerve growth cones pathfind by integrating multiple extracellular cues and I have found that neurons in the Drosophila brain act similarly. I am currently characterising some novel cues, not previously shown to be involved in Drosophila axon guidance and I plan to elucidate how these cues signal to the cytoskeleton. I am using Drosophila as many neurodevelopmental mechanisms are conserved between flies and mammals and many genetic tools (see Q18) are available to rigorously test hypotheses on the mechanisms of neuronal morphogenesis.

Amount: £574,066
Funder: The Wellcome Trust
Recipient: King's College London

Modulation of vasomotor tone by hypoxia in the pulmonary circulation. 07 Nov 2005

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive mechanism which diverts blood from areas of alveolar hypoxia, thereby optimising ventilation-perfusion matching. However, with global hypoxia, (e.g. in COPD), HPV causes detrimental increases in pulmonary artery pressure, increasing morbidity and mortality. The mechanisms causing HPV are controversial. The prevailing hypothesis is that HPV is caused by K+ channel inhibition, leading to depolarisation and Ca2+ influx through voltage-gated Ca2+ channels. Recently, we have been instrumental in developing an alternative model, which proposes that HPV is due to Ca2+ influx via non-selective cation channels and an endothelium-dependent Ca2+ sensitisation. We have also presented evidence that mitochondria act as the O2 sensor, although the intermediate signalling pathways remain obscure.Our major goal for the Programme is to define the Ca2+influx, release and homeostatic pathways involved in HPV. In particular we will explore the involvement of Trp channels, membrane depolarisation, and themitochondria. Our second goal is to establish the mechanisms underlying Ca2+

Amount: £498,929
Funder: The Wellcome Trust
Recipient: King's College London

Function and regulation of the ubiquitin ligase TRAC-1 in T cells. 25 Oct 2005

The ubiquitin ligase TRAC-1 was identified in a screen for modulators of T cell activation and may, given its selective expression in haematopoietic cells, be a key regulator of lymphocyte function. So far, we have found that TRAC-1 inhibits expression of CD69, an early activation marker. Using a variety of functional, biochemical and cell biological experiments, we propose to evaluate the precise role of TRAC-1 in T cells. The key goals are: To characterise the regulatory role of TRAC-1 interactions with membranes and Cbl proteins that were identified in our preliminary experiments. Association with membranes depends on myristoylation, a novel modification for ubiquitin ligases that may regulate access to substrates. Binding to Cbl appears to potentiate TRAC-1 activity. To identify TRAC-1 substrates. This will be approached by two complementary methods: a BacterioMatch two-hybrid screen will be employed to identify TRAC-1-interacting proteins; biochemical analysis will be used to establish specific T cell activation events that are affected by TRAC-1. To analyse TRAC-1 expression in different T cell subsets, which will reveal whether TRAC-1 activity is restricted to specific differentiation or activation states. This study will contribute to two important research areas, those of T cell regulation and ubiquitination.

Amount: £222,308
Funder: The Wellcome Trust
Recipient: King's College London

Factors Defining T Cell Mediated Immunopathology in Psoriasis. 25 Oct 2005

Psoriasis is a significant and common human immunopathology. T cells are thought to play a crucial role as disease effectors, however, factors defining T cell mediated immunopathology during disease development are poorly understood. To be able to address important outstanding scientific questions related to psoriasis pathogenesis, we have developed a novel psoriasis disease model. It represents one of the first available spontaneous human inflammatory disease models. It therefore provides for the first time the basis for the investigation of critical events in early psoriasis development and initiation of T cell mediated immunopathology. We hypothesize that T cell activation and proliferation in psoriasis is dependent on factors such as the local tissue environment, cytokines and resident antigen-presenting cells. We propose to investigate initiation and maintenance of tissue pathology with the following Key Goals: 1. Define the role of local tissue for T cell mediated immunopathology 2. Define the phenotype, function and T cell receptor repertoire of lesional T cells 3. Define key cytokines driving T cell mediated immunopathology The definition of factors involved in T cell mediated immunopathology in psoriasis will broaden our understanding and will also provide new therapeutic targets for of a common human inflammatory disease.

Amount: £1,350,984
Funder: The Wellcome Trust
Recipient: King's College London

The genetics of myopia and refractive error: analysis of highly significant linkage loci. 27 Feb 2006

Refractive error is a common, easily and accurately measured, quantitative trait that is highly heritable, making it an ideal condition to study in an unselected, population-based set of sibling pairs, which is available using the TwinsUK Adult Volunteer Twin Registry. The prevalence of myopia is rising rapidly, and is associated with significant morbidity in those highly-affected. We have previously demonstrated a high heritability for refractive error (0.85) in a classical twin study using a total of 506 MZ and DZ pairs, and published the first genome-wide linkage analysis of this common trait, with 5 loci showing highly significant linkage. The highest linkage peak (LOD 6.1) was on chromosome 11p13, and in a tagged-SNP study we demonstrated significant linkage but not association in the vicinity of the PAX6 gene. In a replication study, we have confirmed another of our significant linkage loci at chromosome 3q26. Fine-mapping of chromosome 11 hasshown a consistent linkage locus at 11q23-24, which exactly coincides with a myopia locus found in an Ashkenazi family study. We propose to further examinethe role for these two promising genomic regions in myopia development, as well as further studying PAX6, by fine-mapping the genes and neighbouring regulatory regions using polymorphic microsatellite markers and dense sets of SNPs in an expanded cohort of 500 DZ twin pairs. We will replicate any resultsfound using two independent samples of MZ twins and unrelated individuals.

Amount: £433,926
Funder: The Wellcome Trust
Recipient: King's College London

Life course influences on women's urinary symptoms and their management during the menopause transition: a prospective birth cohort study. 01 Nov 2005

The MRC National Survey of Health and Development (NSHD) is a nationally representative sample of 2547 women and 2815 men followed up regularly since their birth in March 1946. We shall use repeated data on urinary incontinence collected annually from women study members between the ages of 48 and 54 years, together with life course data on development, health and circumstances, to study the effects of childhood enuresis phenotypes, lifetime weight trajectories and timing of menopausal transition on urge and stress incontinence. Previous, mainly cross sectional studies, focused on adult risk factors, and could not distinguish the effects of menopause from those of age. We shall examine whether changes in urinary symptoms impact on quality of life, independent of potential confounders. We shall study the management strategies that women adopt to relieve urinary symptoms, identifying long-term socioeconomic, behavioural, and health characteristics that distinguish between various management strategies, and between those who seek help or not. This life course study will advance aetiological understanding of midlife incontinence and help clinicians tailor treatment strategies to an individual woman's risk profile. It will inform policy for well-timed interventions designed to improve quality of life for women as they negotiate the menopausal years.

Amount: £101,287
Funder: The Wellcome Trust
Recipient: Medical Research Council

Depression, disability and socio-economic position among older adults 'Left behind' by out-migration: a multilevel study in Kanchanaburi Province, Thailand. 01 Nov 2005

It is suggested that the high level of out-migration of young adults from rural areas in many low-income countries may have negative impacts for older adults (OA). These may include loss of social, instrumental and economic support role for OA which may lead to poor health and social outcomes. If contrast, if migration is effective in diversifying family risks, it should benefit both migrant and non-migrant family members. It is not known whether out-migration of youth is associated with loss of support for OA, or an increased risk of depression or disability. The goals of this study are: 1) To use a historical cohort study to assess the extent to which the risk of depression, disability and low socio-economic position in OA is associated with previous out-migration of one or more of their co-resident children 2) To establish a population cohort of OA to examine the 12-month onset and maintenance of depression and disability, and the 12-month change in socio-economic position, in relation to 'left behind' status and social support 3) To explore any influence of contextual factors on the risk of depression and disability.Kanchanaburi province provides an ideal setting, given a high level of out-migration of youth from family households, and the systematic collection of longitudinal multilevel data between 1999 and 2004 from a representative sample of households as part of the Kanchanaburi Demographic Surveillance Survey.

Amount: £119,367
Funder: The Wellcome Trust
Recipient: King's College London

Does vascular endothelial growth factor have potential as a rescue therapy for alveolar epithelial type II cell damage in acute lung injury (ARDS)? 06 Dec 2005

Acute respiratory distress syndrome (ARDS) is characterized by neutrophilic inflammation with alveolar-capillary barrier disruption, and associated apoptosis of alveolar epithelial cells. Vascular endothelial growth factor (VEGF) plays a central role as a paracrine angiogenic factor in the maintenance of both the integrity and permeability of the alveolar-capillary membrane. In ARDS, low alveolar levels of VEGF reflect the severity of lung injury and recovery is associated with increasing levels over time. In preliminary experiments we have demonstrated that acid and H2O2 induced A549 and human distal lung epithelial cell apoptosis can be ameliorated by the exogenous addition of soluble VEGF isoforms (121,165) up to l hour after acid exposure. Acid and H2O2 induced apoptosis inhibit A549 cell VEGF production and stimulate sVEGFR-1 production, thus reflecting the changes seen in vivo in ARDS. This data suggests that VEGF may have a protective role against epithelial cell apoptosis and pro-VEGF strategies may represent a therapeutic target to promote alveolar-epithelial repair.The purpose of this work is to set up primary human type II cell isolation in Birmingham and to characterise the phenotypic transition to a type I cell phenotype. Using this system, we will test the hypothesis that VEGF acts as an autocrine trophic factor for human adult alveolar type II cells which maintains the integrity and function of the alveolar epithelial monolayer by looking at proliferation, transdifferentiation, surfactant production and monolayer permeability. Under situations of proapoptotic stress where epithelial cell VEGF production is inhibited, exogenous VEGF may be effective as a rescue therapy to promote alveolar epithelial repair. Finally, the effect of exogenous VEGF upon the apoptosis of type II cells produced in response to bronchoalveolar lavage fluid from ARDS patients will be assessed to provide a translational rationale for considering VEGF as a rescue therapy in this catastrophic condition.

Amount: £609,513
Funder: The Wellcome Trust
Recipient: University of Birmingham

The X11 adaptor proteins and Alzheimer's disease. 27 Feb 2006

Work from our and a number of other laboratories has demonstrated that X11a an d X11b inhibit APP processing and Ab production. However, the molecular mechan isms that underlie this effect are not known. This project is to gain insight into these mechanisms. Release of Ab from APP involves proteases termed secret ases and one key goal of this project is to determine whether theX11s influenc e secretase function. A second key goal is to determine whether X11 inhibition of Ab production involves altered trafficking of APP and/or APPsecretases. Fi nally, we have found that the X11s are involved in neuronal copper metabolism and that one of the secretases (BACE1) is a copper binding protein. Disruption to copper homeostasis is believed to contribute to Alzheimer's disease. The f inal goal is to understand further how copper is delivered to BACE1 and whethe r it influences BACE1 function and Ab production.

Amount: £918,022
Funder: The Wellcome Trust
Recipient: King's College London

Autozygosity mapping and identification of recessive disease in genes in consanguineous families. 21 Feb 2006

Autosomal recessively inherited diseases are an important cause of morbidity and mortality, particularly in communities where consanguineous relationships are common. Worldwide at least 1 billion people live in communities were consanguinity rates are >20%. Nevertheless, the identification of recessive disease genes allows reliable diagnostic and carrier testing to be offered to at risk families and, critically, often provides novel insights into the function of gene products and their role in fundamental biological processes. Autozygosity mapping is an effective and efficient strategy for mapping recessive genes in consanguineous kindreds. The combination of autozygosity mapping, identification of conserved haplotypes and mutation analysis of candidate genes has proved to be a most successful approach for characterisation of recessive disease genes and novel insights into pathophysiology and normal cellular processes. We are requesting funding to identify novel disease genes in consanguineous families with neurodevelopmental and ocular autosomal recessive disorders. Thus we will (i) prospectively ascertain and bank DNA on consanguineous families with recessivedisorders, (ii) undertake autozygosity mapping studies in selected families with unmapped disorders, (iii) identify disease genes by a candidate-positional cloning strategy. This study will provide a basis for developing novel diagnostic markers for recessive disorder (expediting the prospect of prenatal and carrier testing) and functional studies of key human developmental pathways.

Amount: £363,049
Funder: The Wellcome Trust
Recipient: University of Birmingham

The neurogenic placodes; a source of restricted sensory neuronal progenitor cells. 27 Feb 2006

Neurogenic placodes are focal thickenings of the embryonic ectoderm that form on the surface of the head of the embryo. It is within these structures that the precursors of the majority of the sensory neurons of the cranial ganglia are specified, and it is from the placodes that these sensory neuronal cells delaminate and then migrate internally to the site of ganglion formation. Importantly, particular placodes generate specific types of sensory neurons. A number of lines of evidence suggest that the cells released by, and migrating from the placodes, may be restricted sensory neuronal progenitor cells. We will use tissue transplantation to determine if the neuronal cells produced by the placodes are committed to particular sensory fates. We will also use in vitro approaches to assess the potential of these cells. We will analyse the role of SoxB1 genes, which are required to maintain neuronal progenitor cells in the CNS, in the formation of placodal derived neuronal progenitor cells. Finally, we will determine if the Sox2 expressing cells in the cranial ganglia of mouse embryos are also restricted sensory neuronal progenitor cells, and whether these cells can generate renewable precursors in vitro.

Amount: £197,530
Funder: The Wellcome Trust
Recipient: King's College London

Genetic dissection of the mood-psychosis spectrum 27 Feb 2006

We propose a programme that builds upon our previous work in mood disorders and psychosis and encompasses clinical and laboratory aspects. We will recruit 600 individuals with an illness characterized by a mix of features typically found in schizophrenia and bipolar disorder - few such individuals have been collected in samples to date but are very important for understanding the relationship between mood disorder and psychosis. We will follow up (by questionnaire and interview) 3000 participants previously recruited to our studies - illness features may vary over time and up-to-date information optimizes analytic power. We will investigate genes already implicated in mood disorders or psychosis by detailed genetic study in 5000 individuals (diagnosed with bipolar disorder, schizophrenia, depression or controls). A major part of our programme is detailed study, within individuals representing a broad range of mood and psychotic illness, of genes implicated in the Wellcome Trust Case Control Consortium (WTCCC) study (a systematic study of the whole genome including 2000 bipolar cases and 3000 controls). In addition to analysing traditional diagnostic categories we will use statistical methods capable of identifying completely new approaches to diagnosis that are biologically valid - we view this as key to our programme. We will pilot new clinical approaches to diagnostic assessment in our clinics. Our focus throughout is on achieving clinically relevant outcomes over realistic timescales.

Amount: £214,583
Funder: The Wellcome Trust
Recipient: University of Birmingham

Induction of calcium oscillations in human sperm by physiological concentration profiles of progesterone and nitric oxide: the role of protein S-nitrosylation and their biological significance. 23 Feb 2006

The mechanisms by which messengers from the egg cumulus complex activate humansperm to be fully competent to fertilise are a crucial aspect of male fertility. Both nitric oxide (NO) and progesterone are secreted by the cumulus and in this proposal we focus on how these two messengers are presented to sperm, how their effects converge to cause oscillations in intracellular calcium concentration and the consequences for sperm function. Our key goals are: 1) To model the concentration profiles of NO and progesterone encountered by sperm as they approach the egg to reveal the likely properties of calcium oscillations in vivo. Different NO donors and progesterone infusion rates will be used to achieve this. 2) To determine within this context if NO acts through protein S-nitrosylation and/or by activation of soluble guanylyl cyclase (sGC). S-Nitrosylation targets will beidentified by the biotin switch assay and proteomics. Specific inhibitors andactivators will be used to probe the role of sGC3) To characterise the physiological consequences of the calcium oscillations. We will concentrate on motility. A complementary package of sophisticated and innovative imaging methods will be employed to look for changes in flagellar waveform concurrent with the calcium oscillations.

Amount: £273,809
Funder: The Wellcome Trust
Recipient: University of Birmingham