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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
Amounts:
£500 - £1,000
£1,000 - £5,000

Results

Regulation of N type calcium channel expression, trafficking and modulation 20 Oct 2005

Voltage-gated calcium channels are essential to numerous aspects of the function of excitable cells. In neurons they are involved in the release of neurotransmitters, and in a number of other processes in which a rise in intracellular Ca2+ is the primary signal. Two very important neuronal subtypes of calcium channels are N-type (CaV2.2) and P/Q-type (CaV2.1), with the former being particularly important at peripheral synapses and neuro-effector junctions, in the autonomic and sensory nervous systems. In nociceptive dorsal root ganglion neurons they are a therapeutic target for anti-nociceptive drugs. The function of these voltage-gated calcium channels may be modulated by several means, for example their expression is controlled by the auxiliary ß as well as a2d subunits, and in the short term they are inhibited by the activation of G-proteins via a variety of G-protein coupled receptors. Over a number of years, my group has examined the properties of cloned calcium channels, expressed both in non-neuronal heterologous expression systems and in neurons. The key goals of the current proposed programme of work relate to four interlinked themes involving CaV2.2 calcium channels: (i) examination of CaV2.2 calcium channel mRNA trafficking and stability, since the mRNA for these channels has particular trafficking motifs in it, (ii) examination of CaV2.2 calcium channel protein trafficking and the role of the auxiliary ß subunits and (iii) study of the mechanism of G-protein modulation of plasma membrane CaV2.2 calcium channels. Finally (iv) we will study the pathophysiological consequences of mis-assembly of CaV2.2 calcium channels. The last theme could also generalise to CaV2.1 calcium channels and may relate to the calcium channelopathy, episodic ataxia-type 2, which is caused by mutations in this channel that are often truncating mutations

Amount: £1,375,208
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

The UCL Fish Facility. 20 Oct 2005

Zebrafish is well established as a leading model organism for studying the genetic basis of vertebrate development and is fast becoming an excellent model for human diseases, for studying nervous system function in vivo, for cell biological, pharmacological and physiological studies and for analysis of gene and genome evolution. The zebrafish research community at UCL is one of the largest and most productive teams of researchers in the field. Zebrafish research at UCL entirely depends upon the UCL Fish Facility, a resource that houses several hundred genetically distinct lines of fish in 2000 tanks spread between two independent systems. However, the success of the research groups at UCL coupled with the increased availability of transgenic and mutant lines of zebrafish means that the current Facilities no longer meet the demands of the user community. Furthermore, the older and larger of the two existing systems is at the point of collapse and urgently needs replacement to avoid potentially catastrophic loss of resources. This application requests funds to replace the existing old facility and to expand the resource through construction of a third system. This project will underpin and allow expansion of research both at UCL and in the wider international community

Amount: £246,385
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

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

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

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

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

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

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

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

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

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

The medical and scientific letters of Dr. David Livingstone online. 22 Nov 2005

Interim (pilot) funding is required to sustain and develop a major online initiative whilst a full grant proposal is researched and written to publish the medical and scientific letters of Dr David Livingstone. The start-up funding (which ends in July) has been provided by the Wellcome Trust Centre for the History of Medicine at UCL and used to support Dr Michael Hawkins whose technical expertise has been essential to initiating the project. We have already established editorial policies and encoding guidelines, transcribed the 70 Livingstone letters held in the Wellcome Library's collection and constructed an alpha version of the site for in-house testing and review. This period of development will involve: Establish an open review process to refine technological policies to ensure best web practice for the beta version of the site. Consolidate links with the National Library of Scotland and Blantyre and also explore links with the archives containing relevant Livingstone material, including the British Library and SOAS. Refine our editorial and transcription policies so that the letters can be put to best scholarly use. Explore online archiving and digital preservation with both UCL and the Arts and Humanities Data Service. Establish outreach potential and identify key means of presenting the material to a wider audience.

Amount: £15,418
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

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