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VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University College London

SONHIA - study of newly diagnosed HIV infection amongst Africans in London. 23 Jan 2006

HIV/AIDS amongst Britain's African communities is a major public health concern, yet to date, relatively little research has focused on this group. This study will increase our understanding of the factors which influence access to, and utilisation of, HIV treatment and prevention services among African communities in Britain. It will also help to inform the development of culturally appropriate HIV health promotion interventions aimed at increasing service uptake within these communities. Plan of investigation: The study population will be all African patients attending in- or outpatient services at selected London HIV treatment centres. To date 7 centres have agreed to participate. The project will consist of two inter-linked components implemented over 2 years: i) A qualitative study amongst a purposively selected sample of newly diagnosed HIV positive Africans employing in-depth interview techniques, and ii) A cross-sectional survey of newly diagnosed HIV positive Africans presenting to specialist HIV services in London. Key workers at each study site will recruit patients and distribute the questionnaires. Dr Burns will perform the interviews. 'Framework' will be used for organising and analysing the qualitative research. Quantitative data analysis will be using STATA 6.0. The questionnaire, topic guide and protocol will be submitted to all appropriate Research Ethics Committees for approval. All patients will be given written information regarding the study and written informed consent will be obtained prior to participation. An African Community Reference Group will be set up to oversee all stages of the study design. Background preparation for the study will be undertaken as part of the MSc dissertation. Study outputs: Peer reviewed publication on health care seeking behaviours among Africans and reasons for delayed presentation; contextual information on healthcare access and utilisation, stigma, onward HIV transmission risk and proportion of HIV infections acquired within the UK.

Amount: £23,380
Funder: The Wellcome Trust
Recipient: University College London

Antigen presentation and dendritic cell function in malnourished children. 15 Feb 2006

Malnutrition has a major impact on the health of children and is responsible for approximately 50% of all childhood deaths, mostly from infectious disease. The precise relationship between malnutrition, immune competence and infectious disease is poorly understood, yet these interrelated factors are the critical determinants of childhood morbidity and mortality. Though neglected in recent years, the association of malnutrition with defects in cell mediated immunity (CMI) is well established. Studies of CMI in malnutrition have focused on T cells, however, central to the successful generation of T cell responses is the ability of the host to present antigen to T cells. The professional antigen presenting cell in humans is the dendritic cell (DC), yet DCs have not been studied in any great detail in malnutrition, partly because the technology for their isolation and culture have only recently been established. Abnormalities of DCs have been described in early life and in association with infections such as HIV and malaria. T cell abnormalities described in severe malnutrition may be secondary to abnormalities of DCs. We propose to study DC function in a group of severely malnourished children on admission to a nutrition ward and then follow their DC function through recovery. The chosen study site in Zambia provides the ideal environment for such a study as the nutrition ward at Lusaka University Teaching Hospital admits 1,800 severely malnourished children a year and has an active research unit. During the study we will (1) characterise the patterns of DC phenotype and function in severe malnutrition, (2) describe the effects of severe malnutrition, HIV and measles on DC function, and (3) describe the impact on DC function of in vitro supplementation with micronutrients, thought to contribute to DC function. This study will provide insights into the mechanism of immune deficiency in malnutrition while also providing a rational basis for the development of novel focused micronutrient supplementation aimed at improving immune function in the severely malnourished child.

Amount: £23,105
Funder: The Wellcome Trust
Recipient: University College London

A combinatorial approach using steroidgenic factor-1 (SF-1, NR5A1) to elucidate novel mechanisms in adrenal and reproductive biology. 05 Jun 2006

We aim to elucidate novel molecular mechanisms involved in human adrenal and reproductive development, and to relate these findings to patients with disorders of adrenal and reproductive function and to variations within normalpopulations. Using microarray and proteomic approaches, we now have the capacity to identify many of the components involved in these systems: the challenge is to focus on those factors relevant to human disease. We will address this using a combinatorial approach (Aims 1-3). In Aim 1, key differentially expressed genes/proteins will be identified in the adrenal, testis and ovary at critical stages of human development between 6-12 weeks gestation. In Aim 2, a subset of important novel genes will be identified by manipulation of the pivotal nuclear receptor sterodiogenic factor-1 (SF-1). InAim 3, genetic loci containing potentially important genes will be mapped using "literature mining" techniques and array analysis of patients with adrenal and reproductive disorders. Taken together, these studies will provideinsight into important biological mechanisms of development and function. Analysis of candidate factors in patients/families with adrenal and reproductive disorders will define novel endocrine syndromes and should identify key factors important in milder clinical phenotypes or physiological variability within a "normal" population (Aim 4).

Amount: £1,215,824
Funder: The Wellcome Trust
Recipient: University College London

Vesicle dynamics and synaptic computation. 01 Jun 2006

This proposal aims to build a quantitative understanding of synaptic function by providing direct links between molecular mechanisms and synaptic computation. We will focus mainly on the cerebellar mossy fibre-granule cell synapse, a model system that is well suited for this purpose. A core aim is todevelop a high resolution optical assay of vesicular release by applying new confocal methods to acute slices from transgenic mice expressing synaptopHluorin. This and recent advances in patching presynaptic terminals will be used to characterize, systematically, vesicle supply, Ca2+-dependenceof release and vesicle recycling. A kinetic model of the vesicle cycle will bedeveloped to elucidate the key determinants of synaptic function. The molecular determinants of specific presynaptic processes will be identified bycomparing model predictions with the behaviour of synapses when protein interactions are altered in transgenic mice or with peptides. Postsynaptically, AMPA receptor function will be examined with localized glutamate uncaging. Key subsynaptic processes will be linked to function by

Amount: £1,280,783
Funder: The Wellcome Trust
Recipient: University College London

Cellular determinants of network dynamics and plasticity in the cerebellar cortex. 01 Jun 2006

Understanding the representation and storage of information in the mammalian brain requires knowledge of how single neurons contribute to generating patterns of network activity and how these patterns are modified by experience. In this proposal I will link cellular mechanisms of synaptic integration and plasticity to the functional behaviour of neuronal networks in the intact rodent cerebellar cortex. Experiments will focus on dendritic signalling in the three major inhibitory cell types in cerebellar cortex: Purkinje neurons, molecular layer interneurons, and Golgi cells. This will be addressed first in slice preparations using a combination of dendritic patch-clamp recordings and imaging of calcium and voltage-sensitive dye signals. These experiments will be linked to the network level by making targeted patch-clamp recordings from labelled neurons in vivo to study their input-output relationships during integration of different types of sensory input (auditory, visual and somatosensory). The spatiotemporal dynamics of activity in identified populations of neurons will be examined via optical imaging in conjunction with 2-photon imaging of calcium signals in single neurons and populations of neurons. Finally, I will use these tools to identify the locus of plasticity in the neural circuits of the cerebellum triggered by behaviourally relevant patterns of activity.

Amount: £1,660,295
Funder: The Wellcome Trust
Recipient: University College London

Cellular and molecular mechanisms of central chemosensory control of breathing. Central chemosensitivity and the reaction theory revisited. 05 Apr 2006

Breathing is the vital rhythmic activity which supports life of an individual by maintaining appropriate rates of oxygen uptake and CO2 elimination. This project addresses one of the most fundamental processes in respiratory physiology - central respiratory CO2 chemosensitivity, which is essential to adjust breathing to the needs of metabolism. Despite significant progress in this field the specific mechanisms of central respiratory chemosensitivity remain largely unknown. In order to pinpoint these mechanisms I propose to usea unique combination of experimental models ranging from cell culture to in vivo animal preparations. Cutting-edge optical imaging and electrophysiological recording techniques will be used to re-evaluate the relative roles of CO2, H+, and HCO3- as potential stimuli for central respiratory chemoreceptors. I shall then identify within the brainstem the populations of cells which respond first to physiologically relevant chemosensory stimulation in physiologically appropriate experimental conditions. To determine how the chemosensory stimulus is transduced I shall use pharmacological approaches to screen through potential intracellular and membrane targets to identify the mechanisms responsible for cellular chemosensitivity. When the candidate central respiratory chemoreceptors and putative chemosensory transduction mechanisms are identified, their physiological roles in mediating respiratory responses to CO2 will be tested using in vivo models.

Amount: £856,154
Funder: The Wellcome Trust
Recipient: University College London

Regulation of lung fibroblast and epithelial cell apoptosis by cyclooxygenase-2 and prostaglandin E2 and their role in the pathogenesis of pulmonary fibrosis. 06 Dec 2005

Pulmonary fibrosis represents the end stage of a heterogeneous group of conditions with poor prognosis and no effective treatment. Recent studies suggest increased epithelial cell (EC) apoptosis and fibroblast resistance to apoptosis contributes to the pathogenesis of fibrosis but the mechanisms are incompletely understood. However, the host laboratory has shown that patients with idiopathic pulmonary fibrosis (IPF) have a decreased capacity to synthesise cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2). COX-2/PGE2 induce fibroblast apoptosis and protect epithelial cells from apoptosis but their role in regulating apoptosis in fibrotic lung is unknown. I therefore hypothesise that the decreased capacity to induce COX-2/PGE2 in patients with IPF contributes to pathogenesis by increasing EC apoptosis and decreasing fibroblast apoptosis. To address this hypothesis I will determine whether COX-2/PGE2 deficiency contributes to human fibrotic lung fibroblast resistanceto apoptosis and induction of EC apoptosis in vitro. I will also examine the effect of COX-2 deficiency on EC and fibroblast apoptosis in an animal model

Amount: £242,197
Funder: The Wellcome Trust
Recipient: University College London

Food as a medical object in Paris, 1670-1815. 10 Nov 2005

The project's central focus is upon the constitution of medical authority over diet in Paris between 1675 and 1815. Against the backdrop of a medical marketplace increasingly dominated by luxury and novelty foods, I will explore the ways in which different medical groups, especially physicians and apothecaries, formulated knowledge about food in relation to rival corporations courting the same clientele. I ask how successful licensed medical practitioners were in reforming domestic eating practices, as well as considering hospitals and soup kitchens as sites for alimentary experiments on the larger scale. While physicians concerned themselves with traditional dietetics, pharmacists turned increasingly to chemical analysis of foodstuffs, producing a successful programme of analysis and industrial exploitation of foods by the First Empire. The project will draw upon recent methodological developments in a variety of fields, including cultural history, anthropology, sociology and literary theory, which offer new ways of writing a history of food and diet. The timescale is chosen to permit a study of the transforming politics of diet during the Revolutionary years. Based on little-known archival and printed materials, the study will provide the first comprehensive account of the various medical understandings of foods and diet in this period.

Amount: £170,483
Funder: The Wellcome Trust
Recipient: University College London

The nature and role of structural changes underlying experience-dependent plasticity in visual cortex. 13 Dec 2005

The rewiring of synaptic connections is considered to be one fundamental way by which the mammalian neocortex stores information and recovers from injury. The likely substrates of cortical plasticity are dendritic spines, since they bear the majority of excitatory synapses and are influenced by synaptic plasticity in vitro. How experience influences the dynamics of spines remains largely unexplored in the living animal. By combining long-term, intrinsic signal imaging and two-photon microscopy in mouse visual cortex, I will correlate the structural dynamics of dendritic spines to functional changes accompanying monocular deprivation (MD). In mice, the shift in ocular dominance (OD) after MD is based on different physiological mechanisms in juvenile and adult animals, is fully reversible, and can be substantially enhanced in adults by MD experience earlier in life. This experimental model therefore provides an excellent context in which to determine how experience-enabled changes in the number, turnover and geometry of spines are affected by age or prior experience. Since LTD and LTP are selectively associated with OD plasticity in juvenile and adult animals, respectively, I will investigate whether the induction of these forms of synaptic plasticity in visual cortex slices induces spine changes similar to those in vivo after MD.

Amount: £566,350
Funder: The Wellcome Trust
Recipient: University College London

Understanding the significance of the AIPL1:NUB1 interaction for photoreceptor homeostasis 20 Oct 2005

Mutations in the pineal- and photoreceptor-specific aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene cause a devastating disease characterized by congenital blindness called Leber congenital amaurosis (LCA). The molecular basis of disease in LCA caused by AIPL1 mutations is not understood. It has been suggested that AIPL1 may function as a chaperone for phosphodiesterase (PDE) and farnesylated proteins. However, mutations in PDE subunits themselves lead to retinitis pigmentosa (RP) and global defects in the processing of farnesylated proteins were not observed in AIPL1 animal models. We have shown that AIPL1 can modulate the nuclear translocation and inclusion formation of the NEDD8 ultimate buster protein 1 (NUB1) and that this activity is affected by certain pathogenic mutations. NUB1 associates with the proteasome and targets small ubiquitin-like protein (NEDD8 and FAT10) conjugated proteins for degradation, providing a functional link between AIPL1 and the proteasome. However, the role of NUB1 in the retina is unknown. The primary goals of this study are therefore i) to determine the molecular mechanisms involved in the AIPL1-mediated regulation of NUB1 nuclear translocation ii) to determine the effect of AIPL1 on NUB1-mediated proteasomal degradation and downstream targets of NUB1 and iii) to determine whether these mechanisms are involved in the processing of PDE and farnesylated proteins by AIPL1, potentially establishing a relational link between the various pathways thus far implicated in AIPL1 LCA. Through these investigations we will gain a better understanding of the molecular mechanisms of AIPL1 LCA, which may identify novel targets for therapeutic intervention.

Amount: £216,710
Funder: The Wellcome Trust
Recipient: University College London

Investigation of the regulation of adipose ADMA during weight change. 07 Nov 2005

Signals from adipose tissue may underlie the relationship between obesity and metabolic diseases through their effects on insulin sensitivity and endothelial function. Asymmetric dimethylarginine (ADMA) is a novel risk factor for cardiovascular disease that inhibits nitric oxide bioavailability and causes endothelial dysfunction. ADMA is primarily cleared by catabolism through the activity of dimethylarginine dimethylaminohydrolase (DDAH). We found that adipose tissue expresses DDAH to high levels and generates significant amounts of ADMA, and the release is modifiable by changes in weight and insulin sensitizers. We propose to investigate the ADMA/DDAH pathway in adipose tissue of DDAH-1 +/- mice, and their wild-type littermates,to explore its relationship to the development of endothelial dysfunction in diet-induced obesity and to assess the reversibility of these changes by weight loss. Adipose tissue distribution and detailed quantification of changes in energy expenditure will be determined, as well as organ cultures toevaluate adipose ADMA secretion. Understanding the effects of the dynamic changes in weight on the adipose tissue DDAH/ADMA pathway and its regulation will increase our understanding of this novel product of this organ, explain the close link between body fat and endothelial dysfunction and provide a valuable basis for designing strategies in the treatment of obesity-associatedpathologies.

Amount: £236,395
Funder: The Wellcome Trust
Recipient: University College London

Synaptic plasticity in hippocampal interneurons: cellular mechanisms. 20 Oct 2005

We have recently found that NMDA receptor-dependent long-term potentiation (LTP) occurs in about half of GABAergic feed-forward inhibitory interneurons in stratum radiatum of the hippocampus. This is only detected if interneurons are recorded in perforated-patch mode, and is not seen if whole-cell pipettes are used, possibly explaining why the phenomenon has not previously been reported. LTP in aspiny interneurons has extensive repercussions for the interaction between memory encoding and information processing in the corticalmicrocircuitry. However, the focus of this application is the underlying cellular mechanisms. Are postsynaptic action potentials required for LTP induction? Can LTP-competent interneurons be identified electrophysiologicallyor anatomically? Can interneurons switch from LTP-incompetence to LTP-competence? What is the role of tyrosine phosphorylation of NMDA receptors? What is the induction cascade downstream of NMDA receptors? How do sub-cellular Ca2+ microdomains relate to pathway-specific LTP in aspiny cells?Do interneurons exhibit NMDA receptor-dependent long-term depression (LTD)? What are the roles of NR2A- and NR2B-containing NMDA receptors, Ca2+/calmodulin kinases, and calcineurin in LTP (and LTD) in interneurons?

Amount: £240,722
Funder: The Wellcome Trust
Recipient: University College London

Isolation and functional analysis of the oral metagenome. 25 Oct 2005

An estimated 800 bacterial species live in the oral cavity of Homo sapiens. The interaction between the commensal microbiota and its human host results in the commonest bacterial diseases of man; dental caries and periodontal diseases. A major bar to studying the orgal microbiota, whichis probably the easiest such microbial community to analyse, is the fact that 50% or more of the bacteria are uncultivable. One method of analysis which overcomes the need for culture and can enable the whole assemblage of oral microorganisms to be studied is metagenomics. We plan to construct a representative metagenomic library of the human oral microbiota and in this preliminary study analyse it for two groups of genes important for the maintenance of oral biofilms and the evolution of virulence and antibiotic resistance. Specifically, this library will be screened to identify genes encoding adhesins important in biofilm formation and for genes encoding systems involved in horizontal gene transfer. Results obtained will help in developing novel anti-plaque strategies and for understanding the ability of oral bacteria to act as reservoirs for antibiotic resistance genes and to spread these resistance genes among themselves and beyond the oral environment.

Amount: £491,528
Funder: The Wellcome Trust
Recipient: University College London

The role of annexin 1 in mediating inward vesiculation within multivesicular endosomes. 17 Oct 2005

We have shown that EGF stimulation promotes multivesicular endosome/body (MVB) formation and inward vesiculation within MVB. MVB formation requires the ESCRT1 component, TSG101, whilst EGF stimulated inward vesiculation within MVB is totally dependent on tyrosine phosphorylation of annexin 1. EGF stimulation promotes the association of annexin 1 with MVB and annexin 1 accumulates with the EGFR on the internal vesicles of MVB. We propose to determine what regulates the enhanced association of annexin 1 with MVBs in EGF-stimulated cells, focusing upon the roles of the N-terminal domain of annexin 1, association of annexin 1 with the EGF receptor and interactions of annexin 1 with inositol phospholipids. We will then determine the molecular mechanisms underlying annnexin 1-mediated inward vesiculation. We will determine the role of the N-terminus of annexin 1 and whether the annexin 1 ligand, S100-A11, or proteolysis of annexin 1 are required. By performing qualitative and quantitative electron microscopy on annexin 1 knockout cells in which annexin 1 mutants have been expressed, and on wild type cells in which dominant negative annexin 1 mutants have been expressed, we will determine at which step(s) in the inward vesiculation process annexin 1 operates.

Amount: £251,686
Funder: The Wellcome Trust
Recipient: University College London

Dissecting the telomere-independent pathways underlying cellular senescence. 17 Oct 2005

Cellular senescence is an irreversible program of cell cycle arrest that is triggered in normal somatic cells in response to a variety of intrinsic and extrinsic stimuli including alteration in telomere length and structure, DNA damage, physiological stress and activation of certain oncogenes. It can compromise tissue repair and regeneration and contribute to tissue and organismal ageing due to depletion of stem/progenitor cell compartments. It can also lead to removal of defective and potentially cancerous cells from the proliferating pool thereby preventing tumour development. The underlying mechanism that controls cellular senescence and the signal transduction pathways involved are not fully understood. We have developed a novel human mammary fibroblast cell system for dissecting the telomere-independent pathways that underlie this process and initiated a systematic analysis to identify the associated changes in the transcriptome. Our aim is to functionally validate genes that we have already identified, extend the transcriptional profiling to encompass all human genes and to carry out a genome wide gain of function RNA interference screen. Collectively, implementation of these strategies will enable us to dissect the telomere independent activities and pathways critical for regulating the finite proliferative potential of normal human cells.

Amount: £250,123
Funder: The Wellcome Trust
Recipient: University College London

Neuronal thalamic gap junctions: identity, location and role in slow EEG rhythms of (patho)physiological states 20 Oct 2005

Synchronized activity among thalamic and cortical neurones underlies the EEG expression of different behavioural state-dependent rhythms, whereas its alterations may lead to EEG paroxysms such as the spike-and-wave discharges (SWDs) of absence epilepsy. Our in vitro studies have identified a key role for gap junctions (GJs) among the glutamatergic thalamocortical (TC) neurones in the expression of synchronized, low-frequency thalamic oscillations, that define two behavioural states, i.e. the alpha rhythm and the slow (<1 Hz) sleep rhythm. In addition, connexin 36 (Cx-36)-based GJs among GABAergic nucleus reticularis thalami (NRT) neurones is known to support synchronized oscillations in this thalamic nucleus in vitro. Here we propose:1. to identify in vivo the contribution of GJs among TC neurones and among NRT cells to the expression of SWDs and of three EEG rhythms: the alpha rhythm, sleep spindles and the slow (<1 Hz) sleep rhythm;2. to identify the sites of GJ coupling in TC and NRT neurones, and the molecular identity of the Cx(s) present in TC neurones using electron microscopy, and triple labelling of dye-coupled neurones and immunocytochemistry with specific Cx antibodies.This multi-disciplinary approach from two laboratories with established expertise in their respective field will shed light into the role of thalamic GJs in EEG rhythms of fundamental importance in health and in one of the generalized epilepsies.

Amount: £170,107
Funder: The Wellcome Trust
Recipient: University College London

Characterisation and functional analysis of Hesx1-interacting proteins in mouse and human. 20 Oct 2005

Hesx1 is a conserved member of the paired-like class of homeobox genes, which is expressed in the rostral region of the developing vertebrate embryo, but isabsent in non-vertebrate species. Hesx1-deficient mice show defects in the forebrain and pituitary gland, and HESX1 mutations are associated with congenital hypopituitarism and septo-optic dysplasia (SOD) in humans. Therefore, it is now established that Hesx1/HESX1 is a critical developmental gene in both mouse and humans. However, little is known about the functions ofHesx1 at a molecular level, i.e., about its regulators, target genes and interacting proteins. To gain further knowledge on the molecular basis of forebrain and pituitary development in mouse and gain insights into the mechanisms underlying congenital hypopituitarism and SOD in humans, we have recently carried out a yeast two-hybrid screen, identified five Hesx1-interacting proteins and partially characterised these interactions. Themain goal of this study is to carry out a detailed characterisation of these interactions with the primary objective of understanding better how Hesx1

Amount: £235,911
Funder: The Wellcome Trust
Recipient: University College London

Perceptual reorganisation in macular disease 27 Feb 2006

Macular Disease (MD) is the leading cause of visual impairment in developed countries. MD causes blind spots in central vision that cannot be cured and for which conventional ophthalmological treatment is of limited benefit. Furthermore, residual vision surrounding the blind spots can suffer from visual distortions and the scotomas themselves can appear "filled in". These perceptual changes are thought to be related to changes in the responses of cortical neurons whose responses recover and remap following damage to their retinal inputs, but analogous evidence in humans is lacking. This proposal examines perceptual reorganization following retinal damage in MD. We develop a new paradigm that will measure if and how remapping occurs in humans with central visual impairment. We use novel quantitative techniques to measure perceptual distortions accurately in patients. We will develop a technique for mapping scotomas with a non-invasive procedure that will be evaluated against existing, slower techniques. These results will be used to develop and test algorithms that geometrically transform images in a manner that will correct the perceptual distortions of the observer. This research aims to increase the efficiency of clinical assessment and maximise residual visual function in low vision observers

Amount: £193,827
Funder: The Wellcome Trust
Recipient: University College London

Wnt signalling in central synaptogenesis. 27 Feb 2006

The formation of synapses requires a proper dialogue between the presynaptic axon and its postsynaptic target cell. Although great progress has been made in understanding the mechanisms that regulate the formation of peripheral synapses much less is known about central synapses. My laboratory has been studying the role of Wnt signalling in the formation of neuronal connections in the vertebrate nervous system. We have demonstrated that Wnts function as retrograde signals that regulate presynapt ic differentiation. Our new studies in the cerebellum have demonstrated that deficiency in Wnt7a and Dvl1, a cytoplasmic protein required for Wnt signalling, results in significant defects in the structure and function of cerebellar synapses. Electrophysiological recordings at the mossy fibre-granule cell synapse reveal a defect in the rate of neurotransmitter release. In the present grant proposal we are taking a multidisciplinary approach that combines transgenic technology, cellular and imag ining techniques and electrophysiology to address the role of Wnt signalling in the assembly and function of central synapses. As Wnt factors are expressed in different areas of the central nervous system, we believe that our studies in the cerebellum will shed light on important general principles used during the assembly of central synapses.

Amount: £296,126
Funder: The Wellcome Trust
Recipient: University College London