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Recipients:
University College London

Results

Characterisation of the physiological roles and pathological significance of endothelium-derived C-type natriuretic peptide: a novel vasoprotective signalling paradigm. 05 Feb 2008

We have identified C-type natriuretic peptide (CNP) as a key endothelium-derived vasorelaxant mediator in mesenteric and coronary resistance arteries, thereby assigning a pivotal role to this peptide in the regulation of local blood flow. Moreover, we have shown that CNP acts as an endogenous protective mechanism against ischaemia-reperfusion injury and regulates the activity of circulating cells and platelets. These seminal observations suggest that CNP maintains a substantial anti-atherogenic/ anti-thrombotic effect on the blood vessel wall. Consequently, loss of this cytoprotective activity may be an important contributor to cardiovascular pathogenesis and therefore represent a novel therapeutic target. This proposal will employ a multi-disciplinary approach including molecular & cell biology, biochemical studies and in vitro/in vivo pharmacology to fully elucidate the (patho)physiological cardioprotective roles of CNP. The key lines of research are: (a) Investigation of the tr anscriptional and biochemical regulation of CNP and functional consequences of this in vivo; (b) Microscopic and electrophysiological analysis of CNP-dependent signalling in vascular cells; (c) Investigation of the mechanisms underlying the anti- & pro- mitogenic properties of CNP; (d) Characterisation of the key physiological and pathological roles of CNP in the cardiovascular system using a novel conditional knockout mouse.

Amount: £476,952
Funder: The Wellcome Trust
Recipient: University College London

Neural Correlates of Auditory Processing Deficits in Auditory Cortex and Thalamus of BXSB/MpJ Mice. 11 Feb 2008

Our aim is to determine whether behavioural deficits in auditory temporal processing are correlated with abnormalities in the responses of auditory cortical and thalamic neurones in BXSB/MpJ mice. These mice are considered to be an animal model for human developmental disorders associated with auditory processing deficits. Approximately half the animals within a BXSB/MpJ litter are ectopic; they have cortical malformations (ectopia) and thalamic abnormalities that resemble those observed in hu mans with developmental disorders like dyslexia. Despite having normal hearing sensitivity, male ectopic mice have difficulty with perception of rapidly changing sounds; such deficits are also typical of dyslexia. We will compare auditory behaviour and auditory cortical and thalamic responses in ectopic male mice with those in non-ectopic males, which do not have auditory processing deficits and therefore serve as genetically matched controls. Key goals are to determine whether neuronal thres holds for gap detection and detection of rapid two-tone oddball stimuli correlate with behavioural thresholds, and whether neuronal minimum response latencies and limits for synchronised following differ between ectopic and non-ectopic mice. These experiments will produce important information about auditory temporal processing in the mouse, and provide insights into the neuronal basis for auditory processing deficits in humans.

Amount: £211,787
Funder: The Wellcome Trust
Recipient: University College London

A genome-wide approach to the characterisation of human and murine DNA methylation. 20 Feb 2008

The proposed project is designed to assay methylation mutants in mouse and humanusing genomic microarray technology. Offspring of mice lacking DNA methyltransferase 3L (Dnmt3L) have no maternal methylation marks at imprinted loci. Genomic array technology will be used to compare mice lacking maternally derived Dnmt3L with wildtype, to identify novel regions of differential methylation and associated imprinted genes. A subset of human patients with transient neonatal diabetes (TNDM) lack maternal methylation marks at a number of imprinted loci. Furthermore, about 30% of patients with SRS show reduced methylation at the H19 DMR. DNA from these patients, like in TNDM, could also be hypomethylated at other loci, providing a rationale for their investigation. We will use methylation-specific array technology to compare a hypomethylated SRS and TNDM samples with control individuals. We will validate regions of novel differential methylation by bisulphite sequencing analysis and confirm novel imprinted genes using allele-specific assays.

Amount: £107,120
Funder: The Wellcome Trust
Recipient: University College London

Oligodendrocyte lineage (Olig) genes in development and disease. 11 Feb 2008

We will investigate the functions and regulation of the transcription factors Olig1 and Olig2. Olig1/2 are important for oligodendrocyte (OL) development and regeneration; Olig2 is also required for specification of spinal motor neurons (MNs) and other types of neurons in the brain. Olig proteins interact with a diverse set of transcriptional co-factors including SoxE proteins, nuclear hormone receptors and homeodomain proteins. We will investigate whether Olig proteins switch binding partner s during successive stages of MN and OL development and whether this contributes to lineage progression. We have evidence that phosphorylation of Olig2 by PKA is required for Olig2 dimer formation and its ability to specify MNs in chick electroporation experiments. We will build on this finding to discover whether and how PKA phosphorylation is involved in MN/OL development. In parallel, we will investigate mechanisms of nuclear translocation of Olig1, which is crucial for generation of new O Ls during demyelinating disease. We have evidence that FGF signalling regulates nuclear accumulation of Olig1 and we will build on this observation. This series of experiments combines biochemical, cellular and transgenic approaches and will provide insights into the biology of Olig proteins and their roles in development and disease.

Amount: £525,692
Funder: The Wellcome Trust
Recipient: University College London

tRNA retrograde transport and HIV-1 nuclear trafficking: a surprising connection. 24 Oct 2007

We have recently discovered that cytoplasmic tRNAs can be transported back into the nucleus in human cells, a process called retrograde tRNA transport, and that this process is exploited by HIV-1 to infect non dividing cells. We hypothesize that specific cellular factors drive nuclear import of tRNAs in human cells and that HIV-1 nuclear import is also promoted by the same factors. We aim to investigate this by: 1) Isolating the cellular factors driving tRNA nuclear import by chromatographic an d genetic approaches. 2) Disrupting their function by stable knock down or generation of dominant-negative mutants and examine the impact on HIV-1 infection in dividing and non-dividing cells. 3) Mapping the viral determinants for incorporation of and interaction with tRNAs with nuclear import activity by the generation of HIV-1 and murine leukaemia virus (MLV) mutants.

Amount: £367,002
Funder: The Wellcome Trust
Recipient: University College London

The role of the mitochondrial endogenous inhibitor, IF-1, in ischaemia and reperfusion injury in the heart. 15 Oct 2007

Mitochondrial dysfunction is central to the pathogenesis of a number of major diseases. At the heart of this proposal is the principle that a decreased mitochondrial membrane potential causes the mitochondrial ATP synthase to operate in 'reverse', switching mitochondria from ATP producers to consumers. The best characterized example of this mechanism is the response of cardiac muscle to ischaemic injury, in which mitochondrial dysfunction defines the borderline between reversible and irreversibl e injury. ATPase activity is modulated by the endogenous inhibitor protein, IF-1, which should be protective by conserving cellular ATP at the expense of allowing the potential to dissipate. As ATP depletion and changes in mitochondrial membrane potential play key roles in defining the progression of ischaemic injury, understanding the processes by which they are regulated is key to understanding the progression of ischaemic injury and so defining therapeutic targets. The proposed experimental w ork will therefore explore the impact of overexpression or suppression (siRNA) of IF-1 protein levels on the evolution of ischaemic injury in cardiac cells and cell lines. Mitochondrial state also defines the pathways of cell death, and so the work will also identify the impact of IF-1 on cell fate.

Amount: £277,607
Funder: The Wellcome Trust
Recipient: University College London

What is the metric structure of the cognitive map? 10 Oct 2007

The study of how hippocampal place cells and entorhinal grid cells represent place largely underpins the cognitive neuroscience of navigation and memory. Previous studies, however, used unrealistic environments in the form of small, two-dimensional enclosures, whereas the real world has an extended, complex, three-dimensional (3-d) structure that complicates navigational processes like path integration. This project will study encoding of 3-d space by manipulating both suface elevation (using sl oped environments including a ramp and a helix) and movement through 3-d, volumetric space, to explore the questions of (1) whether planar place fields and grids are calibrated according to the environment's surface or to the horizontal plane, and (2) of whether in three dimensions, place fields are actually globular and grids are actually lattices in 3-d space. Some of these experiments will exploit newly emerging telemetric technology, which enables recording in spaces too complex for a teth ered animal to explore. The main hypothesis is that the vertical dimension is indeed encoded, but differently from the horizontal ones. The results will not only expand our understanding of the place representation but also shed light on human 3-d navigation processes in aviation, astronautics and undersea exploration, as well as design of artificial navigating agents.

Amount: £161,847
Funder: The Wellcome Trust
Recipient: University College London

A genomewide association study of refractive error in the 1958 British Birth Cohort. 18 Oct 2007

We propose a novel and timely two-stage genomewide association study of refractive error (RE) in a nationally representative population, the 1958 British Birth Cohort (1958BC). Our joint analysis approach will be informed by our recently completed lifecourse epidemiological investigation of environmental determinants [12] and our on-going candidate-gene association study [13], both within this population which provides unique opportunities for studying complex traits. Additional strengths inclu de: -our leadership of the ophthalmic component of the MRC-funded biomedical survey of the 1958BC at 44 years allowing primary myopia phenotype capture without misclassification -robust measurement of quantitative trait of RE in a random subsample (N=2093) -good power to detect modest effects (eg >80% power to detect alleles contributing 10% variance) with likelihood of false discovery within reasonable limits -the extant 1958BC DNA bank funded by Wellcome Trust -prior inclusion of a sub sample of 1958BC in the WT Case Control Consortium [14]. -existing resources for the staff costs of the present proposal -high-throughput high quality genotyping (Illumina s Infinium technology) outsourced to commercial organisations with whom we have established links Our proposal adds value to substantial prior investment in the 1958BC as a national resource for biomedical research, as well as in our work on RE.

Amount: £591,024
Funder: The Wellcome Trust
Recipient: University College London

The human visuomotor grasping circuit: distinct contribution of parietal and frontal areas and their interactions with the primary motor cortex. 10 Oct 2007

Object grasping and manipulation involve a complex parieto-frontal cortical network including the anterior intraparietal area (AIP), the ventral premotor cortex (PMv) and the primary motor cortex (M1). However, the precise operations performed by AIP and PMv and both their lateralization and temporal coupling are still unclear. In addition, how grasp-related information, processed in PMv, is conveyed to M1 to generate an appropriate motor command remains unknown. New methods of assessing activi ty and cortico-cortical connectivity in this visuomotor grasping circuit now make it possible to investigate (1) the nature and timing of the interactions between PMv and M1 to visually guided grasping movements (2) the distinct contributions of AIP and PMv to these movements and (3) how contralateral and ipsilateral cortical areas belonging to the visuomotor grasp circuit interact with each other. We propose to use a novel paired-pulse transcranial magnetic stimulation (TMS) to investigate th e functional connectivity between PMv and M1 during different categories of hand movements or action observation and to document the influence of AIP on these PMv-M1 connections. In addition, we will use magnetoencephalography (MEG) to study the lateralization and timing of those interactions to understand the spatio-temporal flow of grasp-related information within the visuomotor circuit.

Amount: £134,412
Funder: The Wellcome Trust
Recipient: University College London

Regulation of tonic currents through changes in extracellular GABA. 11 Feb 2008

Tonic GABA(A) receptor currents play a major role in controlling neuronal and network excitability. Their magnitude depends on the concentration of extracellular GABA, the regulation and sources of which are still unclear. The aims of this project are to determine the sources for and regulation of extracellular GABA that modulate tonic currents in the hippocampus. Our key goals are to address six hypotheses: 1) Variations in synaptic GABA release affect the tonic current 2) Extracellular GABA is released from astrocytes, 3) Glutamate uptake contributes to the extracellular GABA pool 4) GAD65 contributes to the extracellular GABA pool 5) Rises in extracellular GABA during physiological activity in vivo are secondary to changes in GABA uptake 6) Extracellular GABA varies diurnally and is associated with changes in behavioural state We will take two separate but complimentary approaches and take advantage of expertise in London (patch clamp, EEG), Bristol (in vivo microdialysi s) and Japan (confocal imaging of astrocytes). We will address the question of the potential sources for extracellular GABA using in vitro hippocampal slice preaparations, and we will use an in vivo approach to determine the regulation of extracellular GABA during different physiological states.

Amount: £259,237
Funder: The Wellcome Trust
Recipient: University College London

A Model of the Brain. Cephalopod nervous system as a model for the study of the physiological bases of learning and memory. 02 Apr 2008

I wish to investigate the network of experimental investigations on the anatomical and physiological bases of learning and memory in Octopus vulgaris, performed by John Zachary Young from the early 1940s to the mid 1970s. The choice of the invertebrate Octopus, as a model system for investigating learning and memory processes, was based on a set of basic assumptions, such as the high complexity of its behavioural repertoire, its trainability and the relatively simple and discrete architecture of its brain. Young's experience and the theoretical model of learning he elaborated were widely circulated and had a considerable impact on contemporary neuroscience studies, directly influencing a number of successive theories. I aim to explore the experimental and theoretical roots of Young's theory of the brain, within the context of contemporary neuroscience to underline the impact of his experimental work and of his general theory of memory on the development of a selective account of memor y processes. A second, related goal is to evaluate Young s influence on British medical culture, which, as a Professor of Anatomy at the University College London, he helped renew in an experimental and multidisciplinary direction, together with colleagues such as A. V. Hill and Peter B. Medawar.

Amount: £125,701
Funder: The Wellcome Trust
Recipient: University College London

PAR-1 exerts pro-apoptotic and pro-fibrotic effects following lung injury via the induction of TNF-alpha. 07 Apr 2008

Pulmonary fibrosis represents the end stage of a heterogeneous group of disorders in which excessive interstitial deposition of extracellular matrix proteins leads to airspace obliteration, respiratory insufficiency and premature death. There is strong evidence that procoagulant activity is increased in the lungs of these patients and that activation of the major thrombin signalling receptor, proteinase-activated receptor-1 (PAR1) induces the production/activation of pro-inflammatory and pro-fib rotic cytokines. PAR1 knockout mice (KO) are protected from bleomycin-induced pulmonary fibrosis and recent preliminary data generated by the host centre suggests that murine TNF-alpha expression is attenuated in these mice. There is further evidence that TNF-alpha is crucial for lymphocyte recruitment, TGF- expression, alveolar epithelial cell apoptosis and the development of bleomycin-induced fibrosis. Using PAR1 KO mice and cultured human lung cells, this project will examine the relationsh ip between PAR1 activation and TNF-alpha expression, with respect to the aforementioned parameters, in vivo and in vitro. Human disease relevance will be invoked by performing PAR1, TNF-alpha and apoptosis marker co-localisation studies using lung biopsy material. These studies will provide insights into the crosstalk between coagulation and cytokine networks in fibroproliferative lung disease, potentially identifying novel targets for therapeutic intervention.

Amount: £240,922
Funder: The Wellcome Trust
Recipient: University College London
Amount: £1,666,630
Funder: The Wellcome Trust
Recipient: University College London

Principles of neurotransmitter signal formation in the brain. 09 Apr 2008

Memories are formed trough use-dependent modification of synaptic circuits of the brain. Establishing the cellular basis of such modification, in health and disease, remains a fundamental challenge in neurobiology. Our aim is to elucidate mechanisms through which presynaptic mechanisms and the synaptic environment control formation of fast neurotransmitter signals at central synapses. We are proposing a multi-disciplinary investigation focused on individual excitatory synapses and their microenv ironment in the hippocampal circuitry. Our main research objectives include: - to determine mechanisms through which electrotonic signal propagation and target cell-specific actions of presynaptic kainate receptors affect transmission in the mossy fibre circuitry; - to establish the involvement of glia in use-dependent modifications of glutamatergic signalling; - to determine how the extracellular environment affects diffusion of fast neurotransmitters; - to elucidate presyna ptic mechanisms underlying fluctuations in the release probability and to evaluate the amount of glutamate released by a single synaptic vesicle. The study will capitalise on the existing experimental basis combining single-cell electrophysiology with state-of-the-art multi-photon microscopy techniques and extensive biophysical modelling. The project will also benefit from the first-class research environment and from collaboration with several groups leading in their areas of expertise.

Amount: £1,069,248
Funder: The Wellcome Trust
Recipient: University College London

The neural basis of spatial and episodic memory in humans. 09 Apr 2008

A distributed set of brain regions supports episodic memory, the memory for personal experiences. This brain network overlaps considerably with that associated with navigation and imagination. Surprisingly little is understood about the contributions individual brain areas within this network make in subserving these vital yet distinct cognitive functions. The goal of my research is to understand how these common brain areas, and possibly common processes, underpin episodic memory, navigation an d imagination. To examine this I will study healthy subjects and patients with non-progressive pathologies using fMRI and neuropsychological testing. As well as commonalities I will investigate differences, exploring which additional brain regions are co-opted into this common network to support operations unique to specific functions such as episodic memory. I will complement this systems level approach with a focussed examination of a key region within the common brain network, namely the hip pocampus, as damage to it has the greatest impact on the memory system. I will seek to establish what kind of information it represents using new high resolution imaging and multivariate decoding techniques. I believe that functionally deconstructing the memory system in this way will provide novel and fundamental insights into the mechanisms involved in coding our experiences.

Amount: £1,037,451
Funder: The Wellcome Trust
Recipient: University College London

Epidemiology and treatment of Epilepsy in sub-Saharan Africa. 04 Dec 2007

I plan to conduct cross sectional surveys in five demographic surveillance sites across sub-Saharan Africa, to identify cases of active convulsive epilepsy (ACE). This cohort will be used to determine the prevalence of ACE and the extent of the number of people not receiving treatment (treatmetn gap) in these sites, identify the causes (particularly parasitic diseases that could be prevented) and establish cohorts of people with epilepsy, from which the magnitude and causes of excess mortality a ssociated with epilepsy can be determined. In addition, a community based intervention will be tested through a randomised cluster trial in one of the sites, to reduce the treatment gap and improve the quality of life of people with epilepsy in this area.

Amount: £2,041,821
Funder: The Wellcome Trust
Recipient: University College London

Control of synaptic transmission by scaffold proteins. 28 May 2008

The aim of the first study is to determine if AKAP79/150 is involved in voltage-gated Ca2+ channel regulation in the SNc. AKAP79/150 anchors protein kinase A (PKA), protein kinase C (PKC) and protein phosphatase 2B (PP2B) for regulation of membrane proteins and receptors. Three lines of mice have been engineered with mutations in the AKAP79/150-binding sites for either PKA, PKC or PP2B. Measurements of pacemaking in the SNc in the different breeds of mice will be integrated with studies in cu ltured cells that will include simultaneous electrophysiological and time-lapse imaging recordings of voltage-gated Ca2+ channel signalling. A structural investigation of voltage-gated calcium channel signalling will be initiated in the last year of the fellowship. Both AKAP79/150 and certain members of the membrane-associated guanylate kinase (MAGUK) family can bind CaM and are present in the postsynaptic density (PSD). In this situtation they could potentially orchestrate a rewiring of si gnalling pathways in the PSD following Ca2+ influx and subsequent CaM activation. A second related study will aim to test this hypothesis. RNAi-based experiments in cultured cells will examine the effect of mutation of the CaM-binding site in AKAP79/150, and a proteomic/systems biology investigation to investigate whether CaM activation affects MAGUK valency.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Vestibular representation in the mammalian cortex . 28 May 2008

Every sensory modality has spatial aspects and all vertebrates have a sensory organ dedicated to sensing linear and angular acceleration. I will examine how vestibular input is processed in the hippocampus and associated cortical areas and how it shapes network and single cell activity underlying complex cognitive processes such as spatial navigation. First, I will combine large-scale extracellular recordings with precise measurement of vestibular cues in awake, freely moving animals. I will ana lyze which populations (principal cells, interneurons, grid cells, place cells) are affected by vestibular cues and their contribution to network oscillations. I will also gather stimulus statistics for natural movement to use in the second part. Second, I will combine in vivo whole cell recordings with extracellular recordings in anesthetized animals to examine how vestibular input is coded on the sub- and supra-threshold level in single neurons of the hippocampus and associated cortical areas. This will help understand contribution of single neurons to network oscillations and the representation of the vestibular sense. The anticipated results will help clarify the neural basis of vestibular perception and provide the first steps towards understanding the mechanisms by which the vestibular sense is represented and integrated in the mammalian cortex.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Ravelling, Unravelling. 28 Mar 2008

A creative interpretation of topological and geometric investigations currently being undertaken in the biomedical fields, specifically those relating to packaging and unravelling of material within the human body and as used in the treatment of disease. I will research the twisting and foldings found in the organisation of the gut, in the treatment of medical conditions e.g. aneurysms by intra-vascular coiling, and in the structure of DNA. I will spend the first month of the project exploring different structures, techniques and procedures both at UCL hospital and within the University. Succeeding months will be spent developing a body of new work in the studio whilst maintaining regular dialogue with my advisors. The research will culminate in a public exhibition of new work and a cross disciplinary symposium where a range of speakers and guests from diverse backgrounds will be able to meet and discuss related issues in a public context. Both events will be hosted by the Lighthill Institute of Mathematical Sciences.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University College London

PhD Training Programme in the History of Medicine 29 Aug 2008

PHD Training Programme in the History of Medicine

Amount: £6,600
Funder: The Wellcome Trust
Recipient: University College London