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Funders:
The Wellcome Trust
Recipients:
University College London
Award Year:
2008

Results

Mechanisms of social interaction. 16 Sep 2008

While I am already supported by the Wellcome Trust, my position is currently as a component of the grant awarded to Richard Frackowiak. On the basis of past career and current work it is more appropriate for me to have independent funding. The work I plan will generate a substantial series of linked experiments in a number of cognitive domains. I anticipate that much of the day to day work will be carried out by a series of research fellows and PhD students. Long-term funding for the coordinator of this group is essential to provide continuity and coherence across these projects and to ensure an optimum environment for the training of a new generation of clinical neuroscientists. In addition, a long-term view is needed to ensure that the work of my group continues to feed into and benefit from developments in the other groups that compose the Functional Imaging Laboratory. Functional imaging techniques, particularly fMRI, are going to change and develop rapidly over the next ten years. My past career demonstrates that I have the flexibility to learn and take advantage of new developments as they arise. Long-term funding will obviate the shot-term risks associated with the exploitation of these new developments. My fundamental aim is to increase understanding of brain abnormalities underlying psychosis. Of necessity this is a long-term goal since much work on normal brain function is needed before cognitive paradigms and brain imaging techniques can be applied to the study of psychosis. This work will span at least a ten year period.

Amount: £18,848
Funder: The Wellcome Trust
Recipient: University College London

Modelling functional brain architecture. 16 Sep 2008

The aim of the proposed work is to create models that enable useful and informed inferences about brain function based upon whole-brain electromagnetic and hemodynamic responses. These models are important because they define the nature of the inferences made. Neuroimaging with electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) has an established role in nearly every aspect of cognitive, systems and clinical neuroscience. The data analysis procedures are now relatively sophisticated and ensure valid inferences. However, the statistical models employed are rather simple-minded and have little connection to neurophysiological procecesses, or the principles that might underlie brain function. Conventional models of fMRI are a little more sophisticated than most and rest on linear convolution modes of how changes in neuronal activity are expressed hemodynamically. However, even infMRI, interactions among different neuronal populations or cortical areas are precluded. This is important because the conceptual and biological validity of any forward model, of observed brain responses, places fundamental constraints on the validity and usefulness of inferences about that model. The programme of work described below is an attempt to finesse current models and ground them inneurophysiology and conceptual frameworks derived from machine learning. The hope is that inferences about the parameters of these models are empowered because the parameters have an explicit neurophysiological or mechanistic meaning. If successful, this work will facilitate two key ways of integrating theoretical ideas about large-scale brain function and experimental observations. The first rests on using brain responses to estimate physiologically meaningful parameters of neuronal architectures. The second approach uses data to disambiguate among competing models that embody key theoretical distinctions, formulated in terms of neurophysiology or machine learning; it is a relatively simple matter to identify the most likely model, given the data, using Bayesian model selection.

Amount: £94,552
Funder: The Wellcome Trust
Recipient: University College London

Admixture, ancestry and breast cancer in Brazil: an ethnographic investigation of population genetics, disease risk and identity as the basis for a critical bio-ethics. 05 Jun 2008

The proposed 5 year project examines the ways in which novel scientific efforts to identify and characterise human genetic difference are informing and being influenced by cultural or historical narratives and practices of identity. The Latin American region will be taken as an exemplary case for elucidating the means by which the scientific and social content and context of ancestry and so called genetic admixture are being co-produced . It will focus on admixture mapping initiatives aiming to describe and characterise the variable risk of developing or being a carrier of two different diseases (breast cancer and sickle cell anaemia) in the contrasting regions of Brazil and Argentina. In extending a fledgling body of empirically informed social science research examining the interface between population genetics and different publics the project aims to meet the challenge of using knowledge of human genetic variation for medical interventions in non Euro-American contexts and the urg ent need to more productively align social science and bio-ethics. The study is collaboratively linked to health care institutes in Latin America and long standing expertise in medical/population genetics at UCL, with its strong and growing focus on global health, bio-ethics and issues of distributive justice.

Amount: £326,891
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

The role of stem and progenitor cell populations in skeletal muscle homeostasis, repair and regeneration. 31 Jan 2008

Skeletal muscle repair and regeneration requires the mobilization, proliferation and differentiation of progenitor cell populations. We have developed in vivo mouse models to assay the capacity of satellite cells and other progenitor cells to contribute to skeletal muscle regeneration and to repopulate the satellite cell compartment with functional stem cells. We have shown that a sub-population of the satellite cell pool are stem cells, that have the capacity both to regenerate skeletal muscle and to self-renew and repopulate the satellite cell pool the satellite stem cell (SSC). However, up till now we have not been able to identify and separate SSC from non-stem satellite cells. We now propose to identify novel markers of SSC to allow us to determine which sub-population of satellite cells is SSC. Identification will be reliant on proliferative and metabolic status, and unique cell surface phenotypic markers. We will use these markers to fractionate and purify SSC from dystrop hic and aged muscles and investigate the degree to which the hostile environment within aged or dystrophic muscle is capable of compromising their abundance or their biological function.

Amount: £559,676
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
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

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

Molecular mechanisms of Hesx1 function in early forebrain development. 20 Feb 2008

Hesx1-deficient mouse embryos show a significant reduction of anterior forebrain (AFB) tissue from 8.5 days post coitum (dpc). Recently, we have demonstrated that the absence of Hesx1 leads to a posterior cell fate transformation of AFB. Our data suggest that HESX1 might function to antagonise the activation of Wnt/?-catenin signalling within the AFB. However, the precise molecular mechanism by which Hesx1 modulates this pathway is not known. Moreover, Hesx1 may perform part of its function inde pendently of this signalling pathway, but there is no information on genes potentially regulated by Hesx1. The main goal of this proposal is to expand our knowledge of the role of Hesx1 during forebrain development by combining two complementary approaches: 1. Hypothesis-driven approach. We will dissect at the molecular level how Hesx1 modulates the Wnt/?-catenin signalling pathway within the AFB. We will perform in vitro studies, on transfected cells, and in vivo experiments, on zebrafish an d mouse models with impaired Wnt/??catenin function. 2. Open-ended screening approach. We will perform gene expression profiling studies on three distinct Hesx1-expressing cells to reveal which molecular pathways other than Wnt/?-catenin are regulated by HESX1. We will identify both common and specific genes, which HESX1 regulates in different cell types.

Amount: £947,372
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

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

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

Memory formation and neural activity before an event. 17 Apr 2008

It has recently been demonstrated that brain activity before an event can predict whether the event will later be recollected. This indicates that effective memory formation not only relies on the neural activity elicited by the event itself (as has been known for the past 30 years), but also by activity immediately prior to the event. The aim of the proposed research is to advance our knowledge of pre-stimulus influences on long-term memory encoding. The project has three key goals: 1. To under stand what mental processes are associated with pre-stimulus brain activity; 2. To identify whether pre-stimulus activity can be engaged flexibly and voluntarily; and 3. To ascertain how pre-stimulus activity explains individual differences in memory. A series of experiments is planned in which electrical brain activity is recorded non-invasively from the scalps of healthy human adults while they perform tasks designed to elucidate aspects of encoding. The question of interest is how activity be fore an event varies depending on, among others, type of to-be-encoded information, incentive to encode, and predictability of the experimental sequence. The findings will advance accounts of encoding, and lay the groundwork for future investigations in people with memory deficits (e.g. the elderly and Alzheimer s patients).

Amount: £230,574
Funder: The Wellcome Trust
Recipient: University College London

Signalling by RhoGTPases in the regulation of epithelial cell-cell adhesion and differentiation. 30 Apr 2008

Epithelial cells form polarised cellular sheets by adhering to each other via intercellular junctions. These intercellular junctions mediate adhesion but also regulate polarisation, cytoskeletal architecture and gene expression. RhoGTPases are central regulatory switches in signalling pathways. They regulate multiple cellular processes including those connected to intercellular junctions and are crucial for epithelial polarisation and differentiation. Many RhoGTPase regulators and effectors are encoded in the human genome; however, our knowledge about their functions is limited. The purpose of this proposal is to use the human epithelial cell line Caco-2 as a model to identify RhoGTPase regulators and effectors important for epithelial junction formation and differentiation, as well as to determine how such regulators cooperate to orchestrate epithelial differentiation. Our first goal is to perform a systematic analysis of all known and predicted RhoGTPase regulators and effectors usin g an RNAi library in conjunction with functional assays to monitor junction assembly, polarisation and activity of junctional signalling pathways. Our second goal is to analyse three types of regulators with opposing activities that were identified in preliminary screens to determine how they regulate junctional signalling processes and functionally interact with each other as well as known important RhoGTPase regulators to guide epithelial differentiation.

Amount: £968,351
Funder: The Wellcome Trust
Recipient: University College London

Determinants of physical activity in the UK Millennium Cohort Study 06 Feb 2008

We will measure physical activity using accelerometers at age 7 and again at age 9 in the ethnically diverse UK Millennium Cohort Study and, in a random sample, establish how activity varies by season of year by measuring activity on three further occasions, each a season apart. Two calibration studies will be carried out in 7 and 9 year olds to determine cut-offs defining moderate and vigorous physical activity (MVPA). We hypothesise that MVPA will be inversely related to fat mass, but that th is may vary according to sex and ethnic group. We will test the following hypotheses: that children who are physically active have lower fat mass and less central fat; that children who are overweight or obese by school age are less active at primary school; that more active children have higher subsequent self esteem; that children who skip breakfast, drink sugary drinks or eat high energy snacks have higher fat mass and more centrally distributed fat at age 7; and that Body Mass Index is a no t reliable indicator of fat mass at this age.

Amount: £1,297,375
Funder: The Wellcome Trust
Recipient: University College London

Defining the role of vascular endothelial growth factor (VEGF-A) in commissural axon guidance at the optic chiasm 26 Jun 2008

The co-ordinated patterning of nerves and blood vessels is essential for normal physiological function. This functional integration has its basis in development, but the mechanisms that control the co-patterning of nerves and vessels remain poorly understood. The overarching aim of this proposal is to elucidate the contribution of the archetypical angiogenesis factor vascular endothelial growth factor (VEGF-A) and blood vessels to axon guidance in the central nervous system. Our pilot data p rovides convincing evidence that the VEGF-A isoform VEGF164 and its receptor neuropilin 1 (NRP1) play an essential role in retinal ganglion cell (RGC) axon pathfinding at the optic chiasm, where RGC axons decussate to set up the binocular visual pathways. These findings provide the first evidence for a role of VEGF-A in axon guidance in vivo and identify a classical vascular growth factor as a major player in the establishment of contralateral visual projections. We now wish to extend these fi ndings to establish the precise role of VEGF-A at the optic chiasm. In particular, we wish to determine if VEGF-A acts directly on the growth cones of RGC axons or if physical interactions between nerves and blood vessels underlie the role of VEGF-A in axon guidance.

Amount: £148,775
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

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

Methyl-CpG-binding protein 2 (MeCP2) and the Control of Neuronal Plasticity in Nociceptive Pathways. 16 Sep 2008

Our previously published research suggested that noxious stimulation relieved gene repression by MeCP2, leading to the expression of a number of genes in specific populations of dorsal horn neurons and increased pain sensitivity. This proposal is an investigation of the regulation of persistent pain sensitivity by modulation of MeCP2 activity but is more generally concerned with the role of MeCP2 in the regulation of neuronal plasticity. We will study MeCP2 activity following activation of pai n pathways concentrating on both the phosphorylation of MeCP2 as a mechanism for gene de-repression as well as the inhibition of MeCP2 translation by activity-dependant regulation of microRNA miR-132. We will also study the influence of MeCP2 target genes on persistent pain states and the effects of MeCP2 gene deletion on pain signalling. Specifically, we will investigate the pain phenotype of pre-symptomatic mice that are either MeCP2 male nulls or female heterozygotes . The use of female heterozygotes has the advantage that MeCP2 is deleted in a mosaic fashion throughout the central nervous system allowing us to study the behaviour of adjacent neurons which are either normal or lack MeCP2.

Amount: £266,332
Funder: The Wellcome Trust
Recipient: University College London