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Recipients:
University College London

Results

Identification and characterization of a susceptibility gene or genes for congenital heart disease and oesophageal atresia at human chromosome 17q21.3- q23.3. 12 Jul 2006

Congenital heart defects (CHD) are present in nearly 1% of all newborns and continue to be a significant cause of death in infancy. They may occur in isolation or in association with other birth defects, as with the 22q11 deletion syndrome, for example. Case reports from the human cytogenetics literature point to a susceptibility locus for CHD together with oesophageal atresia at human chromosome 17q21.3-q23.3. This evidence is supported by the finding that mice with a chromosomally engineered deletion within this region,6.8 Mb in size, have CHD, though not oesophageal atresia. The aim of the proposed research is to identify the susceptibility gene for congenital heart defect at human chromosome 17q21.3-q23.3 using further mouse chromosome engineering, BAC 'rescue' of a smaller nested deletion and then targeted mutagenesis of selected candidate genes. In parallel, DNA samples from patients with CHD and oesophageal atresia will be studied by array-based comparative genomic hybridization, with a view to refining the critical region for both of these defects. Subsidiary aims of the project are the identification of the gene responsible for oesophageal atresia at chromosome 17q21.3, and the identification of othersusceptibility loci for CHD and oesophageal atresia elsewhere in the human genome.

Amount: £766,027
Funder: The Wellcome Trust
Recipient: University College London

Brain signatures of auditory information processing in the Degenerative Dementias. 06 Dec 2005

This programme will investigate pathophysiological mechanisms of disordered information processing in dementia using the paradigm of complex sound. It will integrate complementary fMRI, structural MRI, and behavioural (psychoacoustic) measures in clinically, radiologically and genetically-defined populations with the most common cortical degenerative dementias, Alzheimer's disease and frontotemporal lobar degeneration, and in age-matched healthy controls. Mechanisms of elementary auditory pattern analysis will be probed using fMRI, and brain activation profiles will be correlated cross-sectionally and serially with psychoacoustic and other behavioural measures of complex sound processing and with structural MRI. By comparing structural with functional imaging data, and imaging data with behaviour, it will be possible to assess these complementary techniques in relation to one another and in combination. The correlation of complementary disease measures will determine how pathophysiology maps onto structural damage, whether regional brain dysfunction predicts the rate and distribution

Amount: £717,782
Funder: The Wellcome Trust
Recipient: University College London

Accurate assessment of multiple sclerosis pathology using high-field magnetic resonance and quantitative histology. 30 Aug 2006

Using quantitative high-field magnetic resonance (MR) applied to post mortem multiple sclerosis (MS) brain tissue this project aims to establish accurate non-invasive measures for three fundamental pathological features of MS that are potentially of importance for the development of disability and recovery of clinical symptoms in people with this condition: (i) remyelination, (ii) lesions in the grey matter and (iii) gliosis. Furthermore we will explore the possible link between Glutamate as assessed by high-field MR spectroscopy (MRS) and quantitative histological measures (glutaminase activity, axonal count) in MS. Results from this project will have significant impact for the optimisation of MR studies in patients with MS in vivo. It will also facilitate the understanding of the mechanisms that cause disability in MS. T2-weighted (T2W) MR imaging (MRI) of the brain and spinal cord at a field strength of 1.5Tesla is sensitive in the detection of MS white matter (WM) lesions and thereby useful for diagnosis. However, T2W MRI is not specific for the individual pathological substrates of MS, e.g. demyelination, remyelination, axonal loss, gliosis, inflammation. Quantitative MR (qMR) techniques have the potential to be more specific for certain pathological components in MS brain and may therefore improve the monitoring of patients in natural history studies and treatment trials. In order to establish the specificity of qMR measurements, research into the pathological substrates of qMR measures is much needed. Several studies using standard magnetic field strengths have explored the relationship between signal changes detected on MRI and histopathological findings by investigating brain or spinal cord specimens of MS patients. However, the assessment by MR techniques of important aspects of MS pathology, such as lesions in the grey matter or the detailed investigation of WM lesions for signs of remyelination is limited, mainly by the low image resolution at 1.5T.

Amount: £33,101
Funder: The Wellcome Trust
Recipient: University College London

Human T lymphocyte trafficking in large airways and alveoli: the role of lymphocyte adhesion, the epithelial cytoskeleton and the Rho family of GTPases. 05 Jun 2006

In healthy individuals there is a continual flux of leukocytes to and from the alveoli and large airways and this constitutive trafficking is increased in response to infectious and allergenic stimuli. Although much is known of leukocyte adhesion to the vascular endothelium and transendothelial migration. By comparison, little is known of leukocyte interactions with the basal surface of the epithelium or of subsequent passage across the epithelial barrier. Epithelial integrity is maintained by the apically placed tight junction together with the more basally placed adherens junction which, linked via the cytoskeleton, together form the functional apical junction complex (AJC). It is across the AJC that transmigrating leukocytres must pass. Data suggest that leukocytes can interact with epithelial cells to influence the AJC but it is not clear which signalling pathways are involved; although there appears to be a requirement for integrin-mediated adhesion of the leukocyte to the epithelium. Accumulating evidence suggests that the Rho-family of small GTPases (Rho-GTPases) can alter AJC permeability both indirectly, via their known effects on the actin cytoskeleton, and directly via effects on epithelial junctional molecules. In addition, there is evidence that Rho acts downstream of the integrin ligand intercellular adhesion molecule (ICAM)-1 on endothelial cells. We propose that adherent leukocytes interact with epithelial adhesion molecules to initiate downstream signalling events that involve the Rho-GTPases and result in alterations in the actin cytoskeleton and the AJC to facilitate and regulate leukocyte passage. This project will combine the candidate's previous experience in integrin-mediated adhesion, T cell biology and the respiratory epithelium with the expertise of the proposed host laboratory in signalling, cytoskeletal rearrangements and the Rho family of GTPases to address a fundamental question in cellular immunobiology.

Amount: £121,153
Funder: The Wellcome Trust
Recipient: University College London

Integration and plasticity of sensory-evoked synaptic input in single cerebellar interneurones in vivo 13 Dec 2005

Inhibitory microcircuits play a key role in regulating excitability in neuronal networks throughout the brain. However, little is known about the extent to which interneurone circuits are modifiable by sensory experience and the mechanisms involved in such modifications. This project will investigate the plasticity of inhibitory connections in the molecular layer of the cerebellar cortex in vivo by combining two recently developed techniques - in vivo patch-clamp recording and 2-photon imaging - in order to identify the locus of plasticity driven by sensory input in these cerebellar inhibitory circuits. First, whole-cell patch-clamp recordings will be made from Purkinje cells in vivo in order to determine if patterns of sensory stimulation (e.g. whisker deflections) can trigger long-term modification of inhibitory synaptic input to these neurones. Second, we will fill interneurones and Purkinje cells with fluorescent calcium dyes and image dendritic calcium signals in vivo in order to determine if activity-dependent changes are triggered by particular patterns of dendritic calcium signaling. Finally, the experiments will be complemented by compartmental modeling of interneurones and Purkinje cells based on our experimental data. These combined approaches will provide important new insights into how interneurone networks encode changes in sensory experience.

Amount: £245,105
Funder: The Wellcome Trust
Recipient: University College London

Preotease activated receptor-2 in pleural inflammation. 06 Dec 2005

Protease Activated Receptor-2 in Pleural Inflammation Pleural diseases are common in clinical practice. Pleural inflammation is a crucial process underlying the pathogenesis of most pleural diseases, but the mechanisms governing pleural inflammation are poorly understood. Evidence that protease-activated receptor (PAR)-2, a novel seven-transmembrane G-protein-coupled receptor, holds a critical role in tissue inflammation is rapidly accumulating. Our preliminary work showed that activation of PAR-2 in pleural mesothelial cells induced significant release of inflammatory cytokines and rapid pleural neutrophile recruitment in mice, supporting an urgent need to establish the role of PAR-2 in human pleural disorders. Hypothesis and Aims: We hypothesize that activation of PAR-2 in mesothelial cells is crucial to the induction of pleural inflammation in common pleural disease in humans. The aims of this project are: To establish a causal role of PAR-2 in pleural disease using PAR-2 deficient mice. To identify physiological activators (in particular Factor Xa) of PAR-2 in common pleural diseases. To confirm the role of PAR-2 in pleural disease in humans. Significance: This project presents a unique opportunity to combine the host laboratory's expertise on PARs and the applicant's interest in pleural disease, and is supported by promising preliminary work. These studies will provide valuable insight on the PAR-2-mediated organ inflammation. Establishing a causal role of PAR-2 and identifying its activators in pleural diseases may allow the design of novel therapeutic strategies.

Amount: £62,360
Funder: The Wellcome Trust
Recipient: University College London

Distinguishing signal from noise in a sensory cortical network. 10 May 2006

Distinguishing signal from noise in a sensory cortical network One of the most intriguing questions in neuroscience is how networks of neurons in the mammalian brain work together to store information and thus allow learning to take place. This proposal will use in vivo electrophysiological experiments in rodent barrel cortex combined with theoretical work to understand several key questions related to neural coding in mammalian cortex. We will address the following key questions: Do networks use average spike rate to process information or is the precise timing of every spike important? Is the coding scheme modified by the state of the network, in particular by background noise? How many neurons are needed for accurate transmission of information?

Amount: £141,263
Funder: The Wellcome Trust
Recipient: University College London

Electrophysiological and imaging studies of mechanisms underlying brain white matter pathology. 10 May 2006

Electrophysiological and imaging studies of mechanisms underlying brain white matter pathology This project will investigate in depth the mechanisms leading to oligodendrocyte damage in pathological conditions, and some properties of oligodendrocyte precursor cells relevant to normal myelination during development and to remyelination in pathological conditions.

Amount: £141,263
Funder: The Wellcome Trust
Recipient: University College London

The roles of glial cells in models of neurodegenerative disease. 14 Dec 2005

My own work, using fluorescent imaging techniques during the rotation project, showed that Ab increases ROS generation by activation of the NADPH oxidase in BV2 cells and that inhibition of the CLIC1-mediated chloride conductance - with IAA-94, by transfecting cells with an siRNA against the CLIC1 protein or by substitution of Cl with non-permeant anions almost completely prevents that response. We propose that the activity of the NADPH oxidase is limited by charge compensation and that the chloride conductance plays a key role in augmenting the activity of the enzyme by providing a route for the compensation of electron flow across the membrane. CLIC1 is also expressed in astrocytes, but at present we have no data regarding its possible functions. The functions of this CLIC1-mediated chloride conductance, its mode of activation, the means by which its inhibition can reduce ROS production and neuronal death and its potential ubiquity and general importance in glial cell physiology will form the basis of the research to be undertaken during the course of this PhD.

Amount: £4,890
Funder: The Wellcome Trust
Recipient: University College London

An integrated quantitative virological and immunological approach to optimise treatment and define correlates of immune protection against cytomegalovirus in allograft recipients. 25 Oct 2005

In a unique collaboration with transplant clinicians we have produced a paradigm shift in understanding the pathogenesis of HCMV infection. Specifically, we have shown that: a) this virus replicates with rapid dynamics; b) it causes disease in individuals once a critical threshold value of viral load has been reached in the blood; c) patients with rapid replication have a HCMV-specific CD8+ immune defect ("specific interferon gamma impairment; SIGI") which precedes the onset of viraemia. These novel findings will be taken forward in four ways: i) we will conduct randomised controlled trials to optimise treatment based on real time measurement of HCMVviral load; ii) we will determine if SIGI explains why some patients have a slow response to treatment; iii) we will determine if reinfection with a different strain of HCMV can induce SIGI; iv) we will systematically extend immunological studies to determine if other specific immune responses against additional HCMV proteins, restricted by class I and class II HLA molecules, also correlate with full control of HCMV replication.

Amount: £605,793
Funder: The Wellcome Trust
Recipient: University College London

Development and application of fluorescent use-dependent NMDA receptor ligands 27 Feb 2006

An important unresolved question in excitatory neurotransmission is the spatial extent of activation of NMDA receptors following presynaptic glutamate release: is NMDA receptor activation confined to local postsynaptic receptors, or does glutamate spread to and activate extrasynaptic NMDA receptors or even receptors within other synapses in the vicinity? This question has hitherto been addressed only tangentially by applying neuroanatomical and in vitro electrophysiological and pharmacological methods, or by performing simulations constrained by quantitative estimates of presynaptic glutamate release, uptake, diffusion and receptor properties. Fluorescence microscopy in acute brain slices potentially offers a complementary approach, but it has only been applied to probe the down-stream consequences of NMDA receptor activation for Ca2+ transients inside neurons, which are indirectly related to NMDA receptor binding. We propose a new method based on fluorescence microscopy of receptor ligands. We will attach a fluorescent moiety to molecules derived from the high-affinity use-dependent ligand MK-801 (dizocilpine), and screen them for biological activity in a recombinant expression system. We will then apply the most promising candidates to acute hippocampal slices and evoke glutamate release at a subset of synapses to label activated NMDA receptors. By imaging the spatial distribution of fluorescence we will obtain a read-out of the history of activation of NMDA receptors for comparison to electrophysiological signals.

Amount: £126,547
Funder: The Wellcome Trust
Recipient: University College London

Neurotopographics. 26 Jul 2006

Neurotopographics The project brings together a scientist, an architect and an artist to make a film exploring how dynamic patterns of brain activity provide a code for the structure of space. The film will follow the journey of a visitor to an art gallery as seen through the visitor's eyes and from a bird's eye view on an architectural plan. During the journey the activity of brain cells known as 'place cells', 'grid cells' and 'head direction cells' will then be conveyed through a confrontation with sound and colour. The film will invite the audience to consider how their brains represent the world around them.

Amount: £13,000
Funder: The Wellcome Trust
Recipient: University College London

Imaging neuroscience at the Functional Neuroimaging Laboratory (FIL) 20 Sep 2006

The FIL is a prime example of a UK based laboratory that is an established world leader. This application for a Strategic Award is motivated by the need to secure the future of the FIL. The FIL supports a large portfolio of Wellcome Trust (WT) supported programme and project grant research, fellowships and studentships. A Strategic Award will enable the laboratory to retain its highly-skilled core infrastructure support staff; ensure a context of excellence to enable Wellcome Trust funded principal investigators (PIs) to continue producing science that is world class and high impact; and enable the laboratory to provide specific added value. A key example of the latter is in the field of bio-mathematics and data-analysis where our goal is to provide a common platform (extended SPM) for integrating data across distinct imaging modalities including fMRI, magneto-encephalography (MEG) and electro-encephalography (EEG). Finally, a Strategic Award will enable the FIL to provide a theoretical-neuroscience framework that informs both basic and clinically-oriented research into common neurological and psychiatric diseases.

Amount: £6,742,608
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

Prediction of Protein Structure and Function Using Graphical Learning Biology Techniques. 12 Jul 2011

The accurate prediction of biological function on a genome-wide scale promiseswide-ranging benefits in understanding complex biological processes. Such understanding will be a key stepping stone in the development of techniques and pharmaceuticals to target genes associated with disease and their products. Historically, structural insights have provided the most detailed information on biological function, highlighting, for example a specific catalytic mechanism or interactions with partner proteins or other molecules. An in-depth analysis of key functional regions such as those in enzyme active sites, protein-protein binding sites, metal binding sites, and ligand binding clefts, as well as interacting regions between proteins is likely to add significantlyto the repertoire of tools currently available. In this project we will apply some new techniques we have developed to allow correlated mutations in protein families to be detected to the joint problem of protein structure and function By detecting pairs of sites which appear tochange in concert across the evolutionary tree we can infer the possible fold of the protein, residues involved in protein-protein interactions, and residues involved in ligand binding. From this information we hope to recognise a wide range of ligand binding sites, including DNA, RNA, A(TD)P, G(TD)P, sugars, cofactors and even other proteins. For the function prediction work, we may focus initially on predicting DNA and RNA binding sites which are of interest in Dr Savva's lab.

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of genes regulated by S-nitrosylation of HDAC2 during radial neuron migration. 12 Jul 2011

The generation of the laminar structure of the cerebral cortex relies on the radial migration of post mitotic neurons. This proceeds under the control of extremely precise regulatory networks requiring input from multiple extracellular signalling pathways and the co-ordinated expression of nuclear factors that result in specific programmes of gene expression. Recently, in the Riccio lab, we have shown that S-nitrosylation of HDAC2 is required for polarization and radial migration of cortical neurons during the formation of the cerebral cortex. A screen was carried out to identify genes regulated by S-nitrosylation of HDAC2 during cortical neuron migration. Druing this project, 2 candidate genes identified by this screen will be selected and their role in cortical development will be characterised. Key goals which have been set in order to achieve this include the following: 1) Verifying that these genes are upregulated in response to HDAC2 S-nitrosylation. 2) Characterisation of candidate genes expression in vivo 3) Analysis of candidate gene promoter and interaction with HDAC2 4) Characterisation of the function of the candidate genes in cortical neuron polarization and migration, which will include the generation of 2 knockout mouse lines.

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Integrated Structural Biology Approach to the Regulation of PI-Phospholipase CGamma. 12 Jul 2011

The overall aim of the project is to investigate the structure and regulation of the ã-isoforms of phospholipase C (PLC ã), in the context of the interaction with activating growth factor receptors and its interaction with membrane-embedded substrate. Specifically the project will attempt to validate a model for the receptor recruitment to, activation by, and subsequent release from the fibroblast growth factor receptor that has been developed by the co-supervisors of this project [1]. Importantly the work will attempt to determine whether the model, developed using experimental data obtained for PLCã1, is also applicable to PLCã2 for which mutations cause immune deficiency disorders in human patients.

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Cellular and network mechanisms of pattern separation in the dentate gyrus. 06 Jun 2011

This project will investigate how hippocampal dentate gyrus granule cells process synaptic inputs from the medial and lateral entorhinal cortex (MEC and LEC). I will determine how particular activity patterns in MEC and LEC are translated into granule cell population activity in vitro by selectively activating neurons in MEC and LEC using optogenetic stimulation of presynaptic neurons. The results of these experiments will be used to help us interpret subsequent in vivo recordings from granule cells in awake mice navigating in a virtual reality (VR) environment. Both in vitro and in vivo data will be used to construct models to help us to understand the link between cellular processing and behavioural pattern separation.

Amount: £11,835
Funder: The Wellcome Trust
Recipient: University College London