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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

The interplay between the Notch and Wnt signalling pathways in somitogenesis. 20 Oct 2009

The interplay between the Notch and Wnt signalling pathways in somitogenesis This project aims to investigate the potential crosstalk between the Notch and Wnt signalling pathways in the important process of somitogenesis. It is well established now that the Notch pathway plays a crucial role in somitogenesis during vertebrate embryogenesis in a variety of species. More recently it was shown that the Wnt pathway is also required for this process in the mouse embryo. It was also reported that Wnt may play a role upstream of Notch in this process. The first aim of the project is to confirm and extend preliminary findings that Notch may be upstream of Wnt in chick somitogenesis. The second aim of the project is to examine the level of interplay between the two pathways in both the mouse and the chick embryo. Establishing how the Notch and Wnt pathways control somitogenesis will be an important step in understanding how this process is regulated.

Amount: £4,808
Funder: The Wellcome Trust
Recipient: University of Dundee

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

Wellcome Trust Clinical PhD Programme at the University of Dundee: 'Functional analysis of the SLX4 regulator of DNA repair nucleases.' 31 Aug 2010

SLX4 is a highly conserved scaffold protein that binds to, and is thought to regulate, three structure specific endonucleases (SSEs), XPF, MUS81 and SLX1, that play key roles in DNA repair. Depletion of SLX4 from human cells, or a biallelic mutation of SLX4 in cells from a Fanconi Anaemia patient, causes double strand break susceptibility and major DNA repair defects. This is thought to reflect a role for the SLX4 complex in processing branched DNA substrates that arise in DNA repair. SLX4 function is poorly understood at the molecular level. Human SLX4 has several modular domains including a BTB domain. BTB domains mediate protein oligomerization or alternatively binding to cullins. My first aim is to characterise the function of the SLX4 BTB domain. Also, SLX4 forms discrete constitutive subnuclear foci in cells in the absence of DNA damage, and these foci colocalise with XPF. In a Fanconi anaemia patient with low levels of SLX4 protein, XPF foci are absent. This indicates SLX4 localises XPF to nuclear foci in vivo. My second aim is to determine the nature and functional significance of SLX foci.

Amount: £220,113
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust Clinical PhD Programme at the University of Dundee. 31 Aug 2010

Reduced tissue sensitivity to insulin, called insulin resistance (IR), is a major feature of Type 2 Diabetes (T2DM). It also develops many years in advance before T2DM. The majority of the health problems associated with diabetes, such as vascular disease, are likely to begin to develop during insulin resistance. Therefore, it is important to understand why and how insulin resistance develops and how it progresses to diabetes and its complications in some people but not others. Insulin reduces hepatic glucose output in large part by repressing transcription of specific genes, but this process is defective in IR and T2DM. We will generate a transgenic mouse expressing a reporter peptide under the control of a key insulin-regulated gene promoter to investigate hepatic IR and its role in development of T2DM. This peptide is secreted into the blood and urine, and is quantified by ELISA. Therefore peptide levels will be directly related to promoter activity and hence be a surrogate of IR. Peptide measurements will be compared with current methods of assessing IR, including gold standard hormone clamp studies. The novel mouse will be made available, for crossing with models of diabetes, providing a non-invasive, accurate technique for the assessment of IR in vivo. These tools will improve research into the development of IR and T2DM.

Amount: £220,113
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust Clinical PhD Programme at the University of Dundee: 'The translation of quantitative proteomics applied to human disease'. 31 Aug 2010

Recent research at the University of Dundee has led to the development of new methods that use quantitative, mass spectrometry-based proteomics techniques to assay biological mechanisms at a system-wide level. These approaches have been used to screen for novel human proteins involved in regulating basic cellular mechanisms and to assay and annotate protein properties, including subcellular localization, interaction partners, turnover rates and post translational modifications. My research project aims to translate these new state of the art quantitative proteomics methods in a clinical context and to compare results obtained in model human cell systems in the laboratory with changes observed in patient biopsy samples. Using model human cell lines, in which the expression of known tumour suppressor proteins and/or oncogenes can be modulated using small molecule inducers, the Lamond laboratory has identified human proteins which were previously unknown to be associated with mechanisms relevant to cell transformation. This includes the protein products of the human Formin 2 (FMN2) and MRFAP1 genes. I will characterise the expression of both these proteins in human malignancies, assess their suitability as biomarkers and explore how new, advanced proteomics methods can be used to identify other proteins whose expression is altered in human cancer tissue.

Amount: £220,113
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust Clinical PhD Programme at the University of Dundee. 31 Aug 2010

Parkinson Disease (PD) is the second most common neurodegenerative disorder after Alzheimer Disease with significant burdens on individuals, their families, and on society. The discovery that PD follows Mendelian inheritance patterns in some families has led to the identification of PD associated genes. As sporadic and monogenetic Parkinsonism share important neuropathological and clinical features, notably the susceptibility of dopaminergic neurons in the substantia nigra to cell damage, insight into the function of disease causing gene mutations is expected to promote our understanding of key regulatory pathways involved in PD neurodegeneration. Mutations in the Fbxo7 gene have recently been linked to a complex, young-onset Parkinsonian syndrome. Little is known about the physiological role of the Fbxo7 protein or how mutations results in PD-associated neurodegeneration. The aim of my research project is to elucidate the signal transduction pathway of Fbxo7 utilizing standard and human-derived, patient-specific cell lines, but also by generating a new mouse model with human disease-associated knock in and conditional knock-out mutations of the Fbxo7 gene. It is hoped that the findings of the proposed project contribute to a better understanding of PD pathogenesis, the development of new treatment options and possibly the availability of a valid PD mouse model.

Amount: £227,413
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust PhD Programme for Clinicians at the University of Dundee: 'Regulation and function of Nucleoplasmin3 during neuronal differentiation.' 14 Jun 2010

A switch between Fibroblast Growth Factor (FGF) and Retinoic Acid (RA) signalling control onset of neural differentiation in the neural tube with several genes either up or down regulated as the switch occurs. FGF promotes proliferation of neural progenitors and it's down regulation by RA is required for neuronal differentiation. We have recently discovered that Nucleoplasmin3 (NPM3) is down regulated with reduced FGF signalling suggesting it may be co-regulated or is an FGF regulated gene. Nucleoplasmin3 promotes proliferation of mouse Embryonic Stem cells. It's down regulation with FGF signalling raises the possibility that part of the mechanism by which FGF maintains proliferation in the neural tube could be through the function of Nucleoplasmin3. The NPM3 locus is located directly adjacent and upstream to that of Fgf8, a remarkable arrangement that is conserved in different species. NPM3 forms a complex with Nucleoplasmin1 (NPM1) which inhibits NPM1-mediated ribosome biogenesis and this may be involved in cell cycle length and regulation. The role of Nucleoplasmin3 during neural development has not yet been investigated. We aim to understand how signals that direct neural differentiation exert their effects by analyzing the regulation and function of Nucleoplasmin3 during neural development in early chick and mouse embryos.

Amount: £20,825
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust PhD Programme for Clinicians at the University of Dundee: Defining the role of the LKB1-AMPK signalling pathway in cancer and DNA damage. 13 Apr 2010

AMP-activated protein kinase (AMPK) detects changes in AMP: ATP ratio and functions as an energy sensor in cells. Activation of AMPK leads to activation of catabolic processes and inhibition of anabolic processes. In addition to its metabolic effects, AMPK also causes a G1 phase cell cycle arrest. LKB1, a tumour suppressor, is the main upstream kinase that activates AMPK. AMPK also has several downstream targets such as TSC2 and Raptor (mTOR complex) that are implicated in tumourigenesis. Recent evidence suggests that many tumour cells may have down-regulated AMPK signalling. For example, some tumour cells have lost LKB1 expression. The aims of the PhD are to look at the mechanisms underlying loss of AMPK signalling in tumour cells. We will particularly examine the role of the C- terminal tail of LKB1 and the effect of its phosphorylation on AMPK activation. It has been reported that ionising radiation induces ataxia- telangectasia mutated (ATM) kinasemediated phosphorylation of LKB1 at Thr-366. We will look at the effect of this phosphorylation on AMPK activation, which may explain in part how ionising radiation affects cell fate. We will also study the role of DNA damaging chemotherapeutic agents (such as cisplatin and etoposide) on this pathway. We will also develop a mouse model, knocking out AMPK in T lymphocytes which lack one PTEN allele to see if loss of AMPK accelerates development of lymphomas.

Amount: £21,840
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust PhD Programme for Clinicians at the University of Dundee: Neurosteroids: endogenous analgesics? 14 Jun 2010

Peripheral neuropathy affects the normal function of the nerves connecting the spinal cord to muscle, skin and internal organs. Neuropathic pain is often a disabling symptom associated with neuropathy. Diabetes neuritis accounts for ~ 30% of cases of painful neuropathy. Treatment of diabetic neuropathy is often sub-optimal and the underlying aetiology is poorly understood. Both peripheral and central mechanisms are implicated in the development of diabetic neuritis and in particular, spinal dorsal horn neurones display hyperexcitability in neuropathic animal models of type I diabetes. The host laboratory demonstrated in rodents that a naturally occurring analgesic, the neurosteroid 5?3?, potently augments spinal inhibition by enhancing the function of synaptic and extrasynaptic GABAA receptors expressed on lamina II neurones of the dorsal horn. Furthermore, spinal neurosteroid levels are increased in inflammatory pain and consequently act as a protective analgesic. We will employ a multidisciplinary approach to investigate in mice which spinal neurone GABAA receptors mediate the analgesic effects of neurosteroids. The putative role of these steroids as endogenous analgesics in a mouse model of diabetic neuropathy will be determined. Given the recent clinical trial of a drug that enhances neurosteroid synthesis these studies may lead to new therapeutic treatments for neuropathic pain.

Amount: £26,454
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust PhD Programme for Clinicians at the University of Dundee. 20 Oct 2009

The incidence of resistance to antimonials, the first line treatment for visceral leishmaniasis, is rising steadily in Bihar, India. 28% of the tubewells in Bihar district are contaminated with arsenic at levels above the WHO recommended guideline. Arsenite has previously been used in laboratory settings to explore mechanisms of drug resistance to antimony. We propose that the arsenic contamination in the ground water in this area may have induced drug resistance in Leishmania donovani to antimonials. Furthermore arsenic's immunosuppressive properties may increase the severity of leishmaniasis and reduce the efficacy of antimonials through suppression of their immunological mechanisms of action. This study aims to explore the relationship between arsenic contamination of groundwater, leishmaniasis and antimonial resistance by answering the following questions. - Is it possible to induce cross resistance to antimonials in vitro by creating an arsenite resistant strain using concentrations of inorganic arsenic present in tube well water in Bihar? - How does the immunotoxicity of chronic exposure in vivo to arsenic affect the host's immune response to Leishmania? - How does the immunotoxicity of chronic exposure to arsenic in vivo affect the efficacy of antimonials?

Amount: £267,990
Funder: The Wellcome Trust
Recipient: University of Dundee

Wellcome Trust PhD Programme for Clinicians at the University of Dundee: The relationship between visceral leishmaniasis and arsenic contamination of groundwater in Bihar, India. 13 Apr 2010

The incidence of resistance to antimonials, the first line treatment for visceral leishmaniasis, is rising steadily in Bihar, India. 28% of the tubewells in Bihar district are contaminated with arsenic at levels above the WHO recommended guideline. Arsenite has previously been used in laboratory settings to explore mechanisms of drug resistance to antimony. We propose that the arsenic contamination in the ground water in this area may have induced drug resistance in Leishmania donovani to antimonials. Furthermore arsenic's immunosuppressive properties may increase the severity of leishmaniasis and reduce the efficacy of antimonials through suppression of their immunological mechanisms of action. This study aims to explore the relationship between arsenic contamination of groundwater, leishmaniasis and antimonial resistance by answering the following questions. - Is it possible to induce cross resistance to antimonials in vitro by creating an arsenite resistant strain using concentrations of inorganic arsenic present in tube well water in Bihar? - How does the immunotoxicity of chronic exposure in vivo to arsenic affect the host's immune response to Leishmania? - How does the immunotoxicity of chronic exposure to arsenic in vivo affect the efficacy of antimonials?

Amount: £21,695
Funder: The Wellcome Trust
Recipient: University of Dundee

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

Structure and function of the mammalian cell nucleus 22 Apr 2010

My research programme is aimed at understanding how the nucleus is organised in mammalian cells, how specific subnuclear bodies are assembled and regulated and how nuclear structure is related to biological function and to human molecular disease. A major theme of the programme is to use a combination of quantitative in vivo and in vitro techniques to measure dynamic processes in the cell nucleus. To achieve these aims we will focus primarily on studying the dynamic properties of the nucleolus and the nuclear organisation and function of the pre-mRNA splicing machinery. We will also study the role of reversible protein phosphorylation in regulating both nucleolar interactions and the splicing mechanism. We will compare data derived from biochemical experiments carried out using nuclear extracts prepared from cultured cell lines with data on the movement and interactions of proteins in vivo in the same cell lines. We will use proteomic methods to analyse and quantitate the protein composition of nucleoli under different growth and metabolic conditions and we will characterise dynamic interactions in live cells by imaging Fluorescence Protein-tagged fusion proteins. In parallel, we will analyse the organisation and structure of nuclear factors in both transformed and normal human tissue, derived from patient biopsies, to maximise the opportunities for our work on the cell biology of the nucleus to enhance clinical practice.

Amount: £3,113,288
Funder: The Wellcome Trust
Recipient: University of Dundee

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

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

Investigating the functions of the remnant mitochondria of human parasitic protozoa. 06 Oct 2009

We will test the hypothesis that the essential role of microsporidian mitosomes is in cellular Fe/S protein biosynthesis, using subcellular fractionation to provide material for in vitro assays of organelle function, complemented by genetic and biochemical studies, and by quantitative immunolocalisation of key proteins at the electron microscope (EM) level. The ultrastructure of microsporidian mitosomes will be elucidated using sophisticated EM methods, to provide a detailed understanding of mi tosome biogenesis and inheritance during parasite division. The transport proteins used to support the metabolism and energy needs of microsporidian and Giardia mitosomes will be identified and functionally characterized to provide further insights into the functions of these organelles. The characterisation of microsporidian transport proteins that are expressed on the parasite surface will, in conjunction with genomic-based inferences of parasite metabolism, provide clues to parasite-host me tabolic inter-dependencies that may be essential for the growth and survival of these obligate intracellular parasites.

Amount: £512,737
Funder: The Wellcome Trust
Recipient: University of Dundee