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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
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University College London
University of Warwick
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Results

'The influence of network activity on the spatiotemporal receptive fields of mouse V1 neurons'. 15 Dec 2009

The project will investigate the influence of neuronal population activity on receptive field properties of individual neurons in mouse visual cortex at different developmental ages in order to understand how this region of the brain becomes specialised for sensory processing. Particular emphasis will be made on characterising the synaptic mechanisms which shape receptive fields in response to different types of visual stimuli.

Amount: £14,138
Funder: The Wellcome Trust
Recipient: University College London

'Mechanisms of transplanted photoreceptor precursor migration and integration'. 15 Dec 2009

To examine the mechanisms by which transplanted photoreceptor precursor cell migrate into the recipient retina and to compare these mechanisms with those by immature photoreceptors in embryonic development

Amount: £39,182
Funder: The Wellcome Trust
Recipient: University College London

Transport and signalling of cell adhesion molecules and their role in motor neuron survival. 13 Jul 2010

We previously demonstrated that histone H2A is phosphorylated at Ser129 in response to DNA damage by the Mec1p and Tel1p kinases in yeast. Others demonstrated that the analogous residue in mammalian chromatin (Ser139 on histone H2AX) is also phosphorylated in response to DNA damage, and H2AX is a tumour suppressor gene in mice, demonstrating that this is a central event in eukaryotic DNA damage responses. Yet, it is still not entirely clear how this phosphorylation event functions to facilitate survival after DNA damage occurs. We therefore propose to further investigate the function of H2A phosphorylation using three approaches. First, we will systematically characterize the phosphorylation event by analyzing the timing, kinetics, and genetic dependence of phosphorylation in different cell cycle phases, growth phases and ploidy backgrounds. Second, we will examine the fate of phosphorylated H2A. Third, we plan to investigate the effect of phoshpoinositol signalling on H2A phosphorylation and DNA damage responses. Finally, we will integrate these studies with ongoing research in the lab in which we have identified proteins that bind specifically to phosphorylated H2A. Together, these studies will advance our understanding of this highly conserved event in particular and of DNA damage responses in general.

Amount: £5,565
Funder: The Wellcome Trust
Recipient: University College London

A Legal and Ethical Analysis of Research Risks Imposed on Children Involved inCluster Trials With More Than Minimal Risk Conducted Between1999-2010 in Kenya. 03 Jun 2010

1) Review and categorise research risks children are exposed to in different types of 'cluster trials', and explore how these risks are currently regulatedif indeed they are; 2) Test the traditional account of proxy consent and best interests within this context, 3) Examine how the concept of 'minimal' risk is used to see whether it serves to protect or exploit children's multiple vulnerabilities during cluster trials. Key output & goals: mapping and inventory of clinical trials with children andof regulatory framework, critical review of regulatory framework for research involving children, practical suggestions for strengthening local approaches, the engagement of local stakeholders in the review and in the suggestions.

Amount: £134,290
Funder: The Wellcome Trust
Recipient: University College London

Senility before Alzheimer: Old Age Mental Health in British Medicine, Politicsand Culture, 1840- 1914. 10 Jun 2010

This project will explore how 'senile dementia' was understood before Alzheimer in latenineteenth century Britain in medical, political and popular contexts. It will look to the period 1840- 1914 as a time of intense political interest in both the elderly and the mentally ill, and as the time when the word 'senile' shifted, from a value-neutral term describing the general condition of old age, to a more negative term with significant connotations about mental incapacity. Key goals: - To assess how the mental changes of old age were described and explained by psychiatrists. - To examine the relationship between published ideas and practice in increasingly crowded asylums. - To investigate the relationship between the political discourses on pensions, retirement and the welfare of the aged poor, and mental aspects of ageing. - To survey representations of the 'senile' in 'popular culture', and to examine the relationship between these representations, medical models and political concerns. The final product will be a broad survey of the images and meanings of 'old age' in Victorian society and culture, and the place of 'mental capacity and behaviour' within them.

Amount: £77,731
Funder: The Wellcome Trust
Recipient: University of Warwick

Dissecting alpha-synuclein pathology in Drosophila models of Parkinson's Disease: aids to understanding idiopathic Parkinson's Disease. 03 Dec 2009

My research project will use Drosophila melanogaster to model novel mutations in the GBA, PANK2 and PLA2G6 genes known to cause parkinsonism and ?-synuclein pathology in humans, in order to identify common pathogenic pathways in idiopathic PD. This will involve knockout of the GBA, PANK2 and PLA2G6 genes and also expression of PD-associated mutant forms of these genes in Drosophila neural tissue, both in the presence and absence of ?-synuclein expression. These fly models will be characterised, including the effect on longevity, locomotor ability and neuronal viability. I will then study the role of ceramide metabolism in these PD models by comparing the temporo-spatial relationships between these neurotoxic phenotypes and abnormalities in ceramide metabolism. Furthermore I will identify links between ceramide levels and downstream effectors such as mitochondrial, autophagy-lysosomal and proteasomal pathways. In addition, I will determine how loss of function of GBA, PANK2 and PLA2G6 gene products affect the onset and severity of ?-synuclein pathology in flies co-expressing ?- synuclein. In particular, I am interested to determine how these mutations differentially affect the soluble and insoluble pools of ?-synuclein in fly brains. Finally, I will use these fly models as a platform of drug discovery to screen compounds that are predicted to interfere and protect against neurodegeneration by altering ceramide and autophagy pathways.

Amount: £192,279
Funder: The Wellcome Trust
Recipient: University College London

Computational neuroscience of social behavior and psychopathology. 10 Jun 2010

My proposed research program seeks to uncover the computational and neural mechanisms supporting social cognition in humans for the purpose of understanding and treating psychopathologies. The work in this proposal will use neuroimaging, computational models, and later computational approaches to genetic substrates to pursue these goals. We will make liberal use of economically framed social interaction games as probes of both normal and pathological cognition. Our guiding hypothesis in this p roposal is that interpersonal games can be used to uncover functional imaging endophenotypes for important psychopathologies that involve social exchange or social modeling. Such endophenotypes can provide new objective measures to identify underlying genetic correlates, differentiate diagnostic categories or criteria, or provide brain-based assays of treatment strategies.

Amount: £3,212,648
Funder: The Wellcome Trust
Recipient: University College London

Investigation and manipulation of photoreceptor proteostasis. 01 Jul 2010

Defects in protein homeostasis (proteostasis) are associated with neurodegeneration. In the retina, defects in proteostasis can lead to photoreceptor degeneration and blindness. There are currently no treatments for these conditions. This programme of work aims to i) map the photoreceptor response to protein misfolding and aggregation (proteostasis imbalance); ii) investigate the factors that mediate normal photoreceptor protein biogenesis and delineate the mechanisms of protein quality control and degradation; and iii) restore proteostasis in models of photoreceptor degeneration. We will concentrate on the two best characterized diseases associated with photoreceptor proteotoxicity, rhodopsin retinitis pigmentosa and SCA7 polyglutamine expansions. Through an integrated and multidisciplinary approach using cell and animal models we will probe the role of proteostasis networks in photoreceptor degeneration. Importantly, we will also manipulate the factors that facilitate protein folding and degradation to restore proteostasis. Such approaches could then be developed to combat these diseases. These studies may also have broader implications for other forms of photoreceptor degeneration and neurodegeneration in general.

Amount: £1,158,571
Funder: The Wellcome Trust
Recipient: University College London

Temporal regulation of endocrine gene expression - timing in living cells and tissues. 31 Aug 2010

We aim to understand the dynamic regulation of pituitary hormone gene expression in living cells and tissues using valuable transgenic rat models generated over our previous period of funding. Using luciferase or destabilised fluorescent proteins to report promoter activity in real time, we will use pituitary cells and tissue slice preparations to understand the spatio-temporal patterns of gene expression, with 4-dimensional non-linear mathematical modelling approaches to test in what ways cells are transcriptionally coordinated in different circumstances, including fetal and neonatal development, responses to oestrogen, and lactotroph hyperplasia. The transgenic rat models we have generated have shown dramatic induction of human prolactin gene expression in extra-pituitary tissues after inflammatory stress. In addition to detailed assessment of endogenous prolactin gene expression in human tissues, we will use this to identify the pathways involved in prolactin's role in different types of inflammatory response.

Amount: £177,860
Funder: The Wellcome Trust
Recipient: University of Warwick

Mechanisms of Schwann cell myelination and dedifferentiation: relevance to nerve repair and pathology. 18 Feb 2010

In view of the importance of Schwann cell dedifferentiation for nerve pathology/repair, it is surprising how little is known about the relevant transcriptional programmes. Our identification of two transcriptional regulators in Schwann cells, Notch and c-Jun, that control this process is therefore a significant step forward. (A) We will test (i) whether c-Jun-dependent Schwann cell signals control neuronal survival/growth after injury and whether such signals promote neuropathic pain (ii) h ow Schwann cell c-Jun controls breakdown of axon-growth inhibitors and organises cell morphology to generate growth-substrate for axons (iii) the direct transcriptional regulation by c-Jun in Schwann cells of genes important for nerve repair. (B) We will analyse how (i) c-Jun and Notch pathways cross-talk in Schwann cells of injured nerves and (ii) Notch inhibits repair while c-Jun promotes it. (C) Lastly we will test whether, in principle, c-Jun and Notch signalling can be targeted to i mprove pathology in animal models of inherited and acquired demyelinating disease, and nerve regeneration following injury. We will use genetically modified mice, including mice with conditional inactivation of c-Jun, conditional activation of c-Jun, conditional inactivation of Notch, inactivation of the c-Jun/Notch ubiquitin ligase Fbw7 and the transcription factor Olig1, and genetic models of demyelinating disease.

Amount: £1,284,915
Funder: The Wellcome Trust
Recipient: University College London

Defining common mechanisms that guide tangential neuronal migration in the mammalian brain. 08 Oct 2009

Neuronal migration plays an essential role in organising the brain into functional domains. Two distinct modes of neuronal migration have been identified in the developing forebrain: radial and tangential. Three distinct neuronal systems in the forebrain exhibit the tangential mode of migration: cortical interneurons, gonadotropin-releasing hormone (GnRH) neurons and interneuron progenitors of the olfactory bulb. We have been investigating for some time the molecular mechanisms that guide cortic al interneurons and have more recently begun to study the migration of the GnRH neurons. Our work raises the possibility that similar molecular guidance mechanisms control movement of both types of neurons. Here, we propose interrelated lines of investigation to study the involvement of two classes of chemorepulsive molecules (slits and semaphorins) and their corresponding receptors (robos and neuropilins) in the migration of all three neuronal systems. Further, we intend to study how these mole cules interact functionally to orchestrate the complex migratory behaviour of these neurons. The proposed research programme will elucidate novel mechanisms in tangential neuronal migration and shed light on the aetiology of some neuronal migration disorders in humans.

Amount: £904,921
Funder: The Wellcome Trust
Recipient: University College London

Biomedical research into clinical innovation: translation, uptake and impact. 30 Nov 2009

This proposal is to use a unique source for the history of modern medical science, the edited transcripts of the Wellcome Witnesses to Twentieth Century Medicine series, to analyse the process or processes by which science is transformed into accepted medical practice and to identify the major determinants of, and influences on, those processes, ranging from Government policies at one end of the scale to professional demarcation lines at the other.

Amount: £24,153
Funder: The Wellcome Trust
Recipient: University College London

Unravelling the impact of the mite Varroa destructor on the interaction between the honey bee and its viruses 25 May 2010

To investigate the molecular mechanisms of honeybee antiviral defences, to determine the influence of Varroa on these processes and virus diversity, and to identify honeybee genetic markers associated with virus resistance we set up following objectives: O.1. To assess the effect of Varroa mites on virus diversity (DWV, VDV-1 and recombinants) and virus load in the honeybees. O.2. To analyse the influence of Varroa on the honeybee innate immunity (antiviral response), including signalling pathways and RNA interference. O.3. To dissect the influence of genotype variation in bees on the resistance to the immunosuppressive activity of Varroa and the generation of viral genetic diversity. Work summary - Varroa-free honeybee colonies sourced from Colonsay or Skye will be infested Varroa. These Varroa-infested and genetically related Varroa-free control honeybees will be used to study honeybee-Varroa-DWV interactions. - Virus diversity in honeybees and Varroa mites will be analysed using high-throughput Illumina sequencing. qRT-PCR tests for identification of individual components (in particular DWV, VDV-1 and recombinants thereof) will be devised. - Varroa-infested and -free honeybees will be tested for the presence of DWV-specific siRNAs. The diversity of siRNAs will be analysed by Illumina sequencing. - Microarray transcriptional profiling will be used to identify genes/signalling pathways involved in antivirus defence which are suppressed by Varroa. - The functions of the genes implicated in antivirus defence in the honeybees will be tested in RNAi experiments (egg injection with dsRNA). - Honeybee pupae from Varroa-infested and -free colonies will be subjected to multivariate analyses; individual pupae will be tested for the levels of viruses, expression of antivirus-defence genes, virus-specific siRNAs and will be genotyped. The results will be used to develop models of the interaction between honeybees of different genotypes, Varroa and viruses.

Amount: £207,973
Funder: The Wellcome Trust
Recipient: University of Warwick

From single neuron perturbation in vivo to behaviour. 01 Jul 2010

We focus on recording local network activity while perturbing the activity of a single neuron in anaesthetized, awake and behaving animals. Using variety of methods we will maximise the precision, duration and spatiotemporal resolution of the stimulations and the recordings. Theoretical tools will be used to analyse and interpret these measurements. We will use whole cell recordings in vivo to trigger spikes in a cortical neuron and simultaneously record, using tetrodes, single unit activity fro m neighboring neurons. In awake animals we will use a complementary approach for stimulation, electroporating a single neuron with plasmids encoding for light-sensitive ion channels (e.g. ChR2) and photostimulation to trigger spikes. We will quantify how a single extra-spike increases the probability of neurons in the local network to spike. In order to identify the individual cells in the population that participate in the network activity we will combine these methods with in vivo two-photon c alcium imaging of population activity. Finally we will train mice on a whisker positioning discrimination task, and combine all these methods to establish a causal relationship between the participation of a neuron in the task and the effect of perturbing its activity on the performance of the mouse in the task.

Amount: £347,783
Funder: The Wellcome Trust
Recipient: University College London

Molecular regulation of NMDA receptors in midbrain dopaminergic neurones. 01 Jul 2010

The proposed research will investigate the molecular regulation of NMDARs in DA neurones of the substantia nigra. Focussing on the substantia nigra pars compacta, where we have previously shown that the receptors are NR2B and NR2D subtypes, our key goals are to determine: (i) The relative importance of dynamin-dependent and dynamin-independent endocytosis and the role of MAGUK protein - NMDAR subunit interactions in NMDAR regulation at synaptic and extrasynaptic locations. (ii) The importanc e of NR2B and NR2D subunits in the intracellular regulation of synaptic and extra-synaptic NMDARs by kinases and phosphatases. (iii) The effects of NR2D subunit deletion on synaptic receptor density synaptic and on the biophysical properties of synaptic and extrasynaptic NMDAR. (iv) The importance of receptor trafficking and NR2D subunit-containing NMDARs in regulating phasic burst firing of DA neurones. Our approach to distinguish subunit-dependent and subunit-independent mechanisms invo lved in regulating synaptic and extrasynaptic receptors will incorporate high resolution patch-clamp recordings of NMDAR biophysical properties and application of appropriate inhibitors, activators and small interfering peptides to manipulate intracellular signalling molecules.

Amount: £134,873
Funder: The Wellcome Trust
Recipient: University College London

The role of the apelin/APJ pathway in retinal vascular development and pathology. 01 Jul 2010

In an attempt to gain a greater insight into the biological basis of retinal vascular pathology we have conducted a preliminary study to identify candidate genes that may contribute to the vascular changes that occur in various rodent models of retinal disease. This study revealed a significant increase in the expression of the small secreted peptide apelin and its cognate receptor APJ. The aim of this proposal is to investigate, using both in vivo and in vitro approaches, the role of the apelin /APJ pathway in driving the vascular changes observed in these different models of retinal disease and to determine in detail the retinal phenotype in the apelin knockout mouse. We aim to identify the key retinal cell sources of apelin, the factors that regulate apelin and APJ expression in these retinal cells. We will elucidate the signalling pathways mediated by apelin/APJ in endothelial cells and determine whether there is cross-talk with VEGF and/or Norrin/frizzled4/Lrp5 signalling pathways. The effect of modulating these pathways on endothelial cell function will be evaluated. These studies will define the role of the apelinergic system in retinal endothelial cell function in the context of vascular development and pathology.

Amount: £295,334
Funder: The Wellcome Trust
Recipient: University College London

Protein export by the malaria parasite. 27 Apr 2010

In low income countries malaria is a leading cause of death, disproportionately effecting children [1]. Plasmodium, a unicellular eukaryote, causes Malaria and is transmitted to humans via mosquito bites. Symptoms of the disease occur when the parasite enters the bloodstream, where it invades and replicates inside erythrocytes. Within the erythrocyte, Plasmodium resides in a membrane-bounded vacuole, the parasitophorous vacuole (PV). By exporting soluble and membrane proteins across the parasito phorous vacuole membrane, into the cytoplasm and to the surface of the infected erythrocyte, the parasite alters the solute permeability, cytoskeleton, and adhesion properties of its host cell. Many exported proteins are required for immune evasion and parasite viability, making them excellent drug targets. Likewise components of the export machinery itself may also represent novel drug targets. The localization of some exported proteins to the surface of the infected erythrocyte makes them exce llent vaccine candidates. Despite the importance of exported proteins to our understanding and potential treatment of malaria, how proteins are exported across the PV membrane is poorly understood. The goal of this proposal is to gain a mechanistic understanding at the molecular level of how soluble proteins are recognized by the export machinery and subsequently exported across the PV membrane.

Amount: £233,796
Funder: The Wellcome Trust
Recipient: University College London

Stress granules and Caprin-1 in the cochlea: towards a new understanding of how the cochlea copes with stress. . 05 May 2010

The main aim of this project is to understand the role that stress granules play in sensory hair cell survival in the inner ear. It will provide the first characterisation of stress granules, their components and their formation in the mammalian inner ear in vivo. Analysis of mice subjected to different clinically-relevant types of cochlear insult will reveal whether stress-granule assembly is a fundamental response of hair cells to injury and ageing. We have identified a number of hair-cell str ess genes through genetic screens using known essential hair-cell transcription factors. We will now determine whether those hair-cell transcription factors, Pou4f3 and Barhl1 act as stress sensors in hair cells. We have shown that Pou4f3 regulates Caprin-1, a recently identified component of RNA granules and that Caprin-1 is present in stress granules during hair cell damage. We will now identify Caprin-1 s binding partners, determine the role that Caprin-1 plays during hair-cell stress in vitr o and generate a conditional knockout mouse to determine whether Caprin-1 regulates hair-cell survival in vivo. We will utilise in vitro manipulations of Caprin-1 and other stress granule components to test whether such interventions can improve hair cell survival during cochlear stress.

Amount: £347,028
Funder: The Wellcome Trust
Recipient: University College London

Transcriptional regulation of human T cell differentiation. 08 Feb 2010

CD4+ T cells differentiate into a number of effector types that define the immune response to different pathogens. Differentiation into specialized effectors is linked to changes in chromatin structure at key genes and transcription factors have been identified that are critical for this process. These epigenetic modifications provide a memory of cellular state passed onto cellular descendents. T cell effector types are also remarkably plastic and this combination of specificity and plasticity i s likely to be critical for the normal regulation of T cell effector function. We will identify the changes in histone methylation that occur across the genome during differentiation of primary human CD4+ T cells. We will test the hypothesis that lineage-specific gene expression is regulated primarily at the level of transcriptional elongation and determine the role of master regulator transcription factors. From these data, we will develop a conceptual framework that explains the specificity an d plasticity of the helper T cell response. All aspects of this proposal are underpinned by significant amounts of preliminary data. We will define these mechanisms with a combination of established in vitro and in vivo genomic, genetic and biochemical methods and this work will significantly enhance our understanding of human disease processes.

Amount: £237,518
Funder: The Wellcome Trust
Recipient: University College London

Signal integration by annexin 2 during retinal phagocytosis. 04 Feb 2010

Our previous WT-funded work has shown that annexin 2 is required for the prompt circadian activation of Src and FAK in retinal pigment epithelial cells, that is in turn required for the phagocytosis of shed photoreceptor outer segments. Annexin 2 is regulated by phosphoinositides, calcium and tyrosine phosphorylation, but it is not known how these second messengers and tyrosine phosphorylation combine to regulate annexin 2 function and thus retinal phagocytosis. Our key goals are to i) exami ne annexin 2 tyrosine phosphorylation during retinal phagocytosis in the broader context of total cellular tyrosine kinase activation, ii) specifically investigate the spatial and temporal relationship between annexin 2, Src, FAK and Mer during phagocytosis, iii) use annexin 2 mutants in cell culture and in vivo (in AAV vectors) to determine how second messengers and tyrosine phosphorylation combine to regulate annexin 2, and iv) evaluate the effects of expression of these mutants on retinal and visual function. The work will be conducted in control and annexin 2 KO mice, and in cultured cells using live cell imaging. In addition we will use existing rodent strains to examine annexin 2 in RPE cells lacking FAK and Mer.

Amount: £290,342
Funder: The Wellcome Trust
Recipient: University College London