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Results

Life course influences on women's urinary symptoms and their management during the menopause transition: a prospective birth cohort study. 01 Nov 2005

The MRC National Survey of Health and Development (NSHD) is a nationally representative sample of 2547 women and 2815 men followed up regularly since their birth in March 1946. We shall use repeated data on urinary incontinence collected annually from women study members between the ages of 48 and 54 years, together with life course data on development, health and circumstances, to study the effects of childhood enuresis phenotypes, lifetime weight trajectories and timing of menopausal transition on urge and stress incontinence. Previous, mainly cross sectional studies, focused on adult risk factors, and could not distinguish the effects of menopause from those of age. We shall examine whether changes in urinary symptoms impact on quality of life, independent of potential confounders. We shall study the management strategies that women adopt to relieve urinary symptoms, identifying long-term socioeconomic, behavioural, and health characteristics that distinguish between various management strategies, and between those who seek help or not. This life course study will advance aetiological understanding of midlife incontinence and help clinicians tailor treatment strategies to an individual woman's risk profile. It will inform policy for well-timed interventions designed to improve quality of life for women as they negotiate the menopausal years.

Amount: £101,287
Funder: The Wellcome Trust
Recipient: Medical Research Council

Exploring Normality - Developing a Scientific Model of Disability. 26 Jul 2006

Exploring Normality - Developing a Scientific Model of Disability Dr Ju Gosling aka Ju90 will undertake a part time placement over one year at the National Institute for Medical Research (NIMR) in North London. She will be in ongoing discussion with limb development researcher Dr Malcolm Logan and neuroendocrinologist/paediatric clinician Dr Evelien Gevers as well as others. The placement will focus on social perceptions of normality from medical, research, disability, art and other perspectives. Working toward a book on this subject, this placement will also produce photographic, sound and web based text works by the artist. A major collaborative hope is to develop a scientific model of disability.

Amount: £15,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

A genetic dissection of brain and heart phenotypes in the Tc1 transchromosomic mouse model of Down syndrome. 27 Jun 2006

Down syndrome (DS) arises from trisomy of human chromosome 21 (Hsa21), and thus from an abnormal gene dosage of unmutated Hsa21 genes, giving rise to the many phenotypes that are found in DS individuals. However, it remains unknown which genes need to be present in three copies to cause particular phenotypes, such as heart malformation. The genotype-phenotype relationships in DS have proven extremely difficult to tease out, yet are important as individuals with DS succumb to a range of disorders such as dementia, heart disorders, etc., that may be treatable if we know which cellular pathways are involved.We have recently established a novel transchromosomic mouse model of DS termed Tc1, which carries a freely segregating Hsa21. Tc1mice have defects in behaviour, synaptic plasticity, and brain and heart development. We now propose to investigate these brain and heart defects in much more depth and to combine this with chromosome engineering of mouse embryonic stem cells to dissect the molecular genetics of these phenotypes. We will combine our knowledge of mouse embryonic stem cell manipulation and the creation of transchromosomic mice, with specialist knowledge from three laboratories studying brain and heart. Working together, we will initially map regions of Hsa21 and ultimately identify specific genes which when present in three copies are responsible for the brain and heart phenotypes.

Amount: £717,833
Funder: The Wellcome Trust
Recipient: Medical Research Council

How do pattern defects cause apoptosis in developing tissues?. 30 May 2007

Tissue homeostasis depends on the appropriate integration of cell proliferation, cell differentiation and apoptosis. The apoptosis program is activated to remove superfluous, mis-specified, or genetically damaged cells. I plan to investigate the mechanisms that activate apoptosis in cells that are mis-specified during development. To address this question, I will first determine the spatial pattern of cell death in Drosophila embryos in response to the lack or excess of Wingless signalling. I wi ll also look at the behaviour of these cells under conditions that prevent them from undergoing apoptosis. In parallel, I will use existing databases and microarray analysis to search for genes that could mediate the response to mis-specification. One possibility is that cell surface molecules will be involved, allowing cells to display and compare their state of specification within a field. I expect such genes as well as genes encoding components of the signal transduction machinery to come ou t of my search At the end of my fellowship I will initiate the functional analysis of these genes.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Study of papillomavirus latency in a rabbit model. 12 Jul 2007

We intend to establish that rabbit oral papillomavirus (ROPV) can establish a latent infection following experimental infection as is the case with COPV and CRPV, that leads to papilloma formation followed by immune-mediated regression. Having achieved this, we propose to characterise mechanisms of viral latency at the molecular, cellular and immunological level, potentially identifying possible targets for therapeutic intervention. Further, we aim to identify the cells within which the vi rus remains latent. We intend to determine whether or not a latent infection in the ROPV model can be subsequently reactivated by immunosuppression, and to characterise the molecular and immunological events which subsequently occur. Finally, we hope to identify a papillomavirus in wild mice, which is capable of causing a productive infection in laboratory mice. This will expand future possibilities of research on latency and offer better opportunities for developing therapeutic and proph ylactic vaccinations than the current model systems do.

Amount: £204,354
Funder: The Wellcome Trust
Recipient: Medical Research Council

Life course and trans-generational influences on cardiovascular disease and cancer 05 Dec 2006

CVD and cancer are major causes of death and morbidity in developed countries; they are assuming increasing importance in non-industrialised societies. Risk factors measured in middle- and older-age do not fully explain socioeconomic or geographical differentials in these chronic diseases, so implicating processes occurring earlier in life, and even between generations, in the aetiology of CVD and cancer. A small number of recent studies have identified some potential pre-adult risk indices for later CVD and cancer. I plan to expand this evidence base by examining the role of new and emerging physiological, behavioural, socioeconomic and psychological risk factors (and their cross-generation transmission) in later disease risk. To do so I will utilise data from a series of studies from low and high income countries. During the tenure of the fellowship, in collaboration with colleagues, I will produce manuscripts for publications in high-impact, peer-reviewed journals; present my work at international meetings; supervise/teach post-graduate students; and seek funding for further data collection in selected studies. This body of work may be used in interventions in childhood and young adults aimed at reducing the burden of CVD and cancer in later life.

Amount: £574,957
Funder: The Wellcome Trust
Recipient: Medical Research Council

Pitch perception by cochlear implant users 12 Oct 2006

Cochlear implants (CIs) allow previously-deaf patients to understand speech in quiet, but are very poor at encoding pitch. This results in poor speech understanding in noise, and in reduced enjoyment of music. A major limitation is that most CI users cannot derive pitch from changes in electric pulse rate above about 300 pps, whereas normal-hearing (NH) listeners exploit temporal cues up to much higher rates. We will use both psychophysical techniques and a measure of auditory-nerve activity, the electrically evoked compound action potential (ECAP), to investigate this upper-rate limitation. We (i) Examine whether the alternating-amplitude pattern, previously observed in the ECAP to high-rate pulse trains, is responsible for the limitation. We will study manipulations that should reduce the alternation and compare the effect on the ECAP with that on pitch tasks, (ii) Study instances where pitch varies non-monotonically with rate, again using a combination of behavioural and ECAP measures, (iii) investigate whether the high-rate limitation can be overcome by concurrent stimulation of multiple electrodes. Finally, we investigate the match between the place and rate of stimulation that, it has been suggested, is important for good pitch perception.

Amount: £146,417
Funder: The Wellcome Trust
Recipient: Medical Research Council

Graded hedgehog signalling in the neural tube: mathematical modelling of a developmental multistate switch. 01 Nov 2006

Morphogens are graded positional cues that control cell fate specification in many developing tissues. The activity of Sonic Hedgehog (Shh) in the spinal cord represents an example where progress has been made in understanding morphogen activity. In response to graded Shh signaling, distinct neuronal subtypes emerge in a precise spatial order from progenitor cells arrayed along the dorsoventral axis of the spinal cord. Cross-repressive interactions between responding genes appear to ensure the g eneration of discrete changes in gene expression. Thus, graded Shh signalling controls a multiway differentiation switch composed of concentration-dependent gene-regulation and a network of interactions between responding genes. Here we propose to analyse this process using a combination of mathematical and developmental biology. The mechanisms by which a gradient of Shh signalling is formed, refined and interpreted are not well understood. We will construct a mathematical model which describes the formation and interpretation of the Shh gradient. In vitro and in vivo experiments in embryos will be used as the foundation of the model and to test key predictions. The resulting model will be used to analyse how graded Shh effects a multiway switch and to identify critical features of the mechanism that confer precise and reliable patterning.

Amount: £173,324
Funder: The Wellcome Trust
Recipient: Medical Research Council

The role of IL-17 in type I diabetes in NOD mice. 19 Oct 2006

Type 1 diabetes is considered a Th1 mediated disease. Recently the role of Th1T cells in a number of autoimmune diseases, notably EAE and arthritis, has been questioned, since it became clear that the principal effector cells in these diseases are a novel subset of CD4 T cells, termed Th17 T cells, which as we have recently shown differentiate from naïve precursors in response to acombination of TGFb1 with IL-6, further amplified by TNFa and IL-1b?. Th17 T cells and Th1 T cells are mutually inhibitory and any differentiation step that favours the development of Th17 will compromise generation of Th1.The involvement of IL-17 in diabetes has so far not been addressed and there are observations that suggest Th17 might not be pathogenic in diabetes and that onthe contrary their induction at the expense of Th1 might be beneficial. We will attempt to causally link the protective effect of immune modulators such as schistosome egg extract and zymosan to differential activation of DC that would favour the development of Th17 at the expense of Th1 cells and predict that Th17 cells do not cause pathology in diabetes, but may rather interfere with pathological Th1 responses.

Amount: £158,931
Funder: The Wellcome Trust
Recipient: Medical Research Council

Structural basis for the role of K-homology Splicing Regulator Protein in mRNA turnover. 27 Feb 2007

mRNA stability is an important parameter in determining the level of gene expression and can be selectively regulated. Adenine uracil-rich elements (AREs)-mediated mRNA decay (AMD) modulates the stability of many mRNAs that encode transcription factors and other regulatory proteins. In AMD, ARE-binding proteins (ABPs) recruit the exosome to long AREs embedded in the 3 untranslated region (3 UTR) of selected mRNAs. However the specificity of ABP-ARE interactions (and therefore of exosome recruit ment) is poorly understood at the molecular level. It seems likely that the recognition of the long ARE sequences by ABPs is based on multiple protein-RNA interactions and that RNA structural elements play a role. This hypothesis is supported by functional studies on several ABPs, but also by our preliminary biophysical results with the functionally well-characterised K-homology Splicing Regulator Protein (KSRP). These results also indicate that interactions between the domains of the protein pl ay a role in recognition. We want to solve the structure of the RNA binding region of KSRP alone and in complex with both single stranded and partially structured RNA targets. The fundamental question we wish to answer is how ARE recognition is linked to the RNA structure and to the interactions existing between protein domains.

Amount: £275,812
Funder: The Wellcome Trust
Recipient: Medical Research Council

Evaluation of the efficacy of hydroxychloroquine in decreasing immune activation and viral replication in asymptomatic HIV-infected patients . 15 May 2007

The proposal is to conduct a randomised, double-blind, placebo-controlled clinical trial of hydroxychloroquine for the treatment of early stage HIV infection. A total of 90 asymptomatic, antiretroviral na ve HIV-infected patients with CD4 T-cell counts greater than 400/ L and with no major contraindications to treatment will be recruited from major HIV treatment centres in or around London. Patients will be randomised to receive hydroxychloroquine 400mg/day or matching placebo to be taken once d aily by mouth for 48 weeks, and will be followed at regular (1 to 3 monthly) intervals for assessment of efficacy and safety. Efficacy parameters include measurement of T-cell activation, proliferation and apoptosis, viral load and absolute CD4 T-cell counts. Safety assessments include standard clinical and laboratory toxicity monitoring as well as rigorous observation for evidence of retinopathy. The primary endpoint is the change in CD8 T-cell activation at week 48 compared to baseline, and th e main secondary endpoints are change in viral load and CD4 T-cell count at week 48 compared to baseline (analysis will compare change in hydroxychloroquine and placebo groups). The study has 90% power to detect a 25% reduction in CD8 T-cell activation and a 0.4log reduction in viral load in the hydroxychloroquine group.

Amount: £246,685
Funder: The Wellcome Trust
Recipient: Medical Research Council

Structural and functional analysis of interactions involving the nuclear transport machinery that generate nuclear RNA and protein export and orchestrate mitotic spindle assembly. 01 Nov 2006

My overall goal is to understand how nuclear transport factors interact with their cargoes and other components of the transport machinery to (i) export macromolecules from the nucleus during interphase and (ii) orchestrate spindleassembly during mitosis. These aims share a common focus on nuclear transportfactors and their interaction with different partners, and build on my previous work that established the structural basis for key steps in the nuclear protein import cycle. Molecular recognition by transport factors is fundamental to the nuclear export of proteins, mRNA, pre-microRNA, and tRNA, and is also crucial in mitotic spindle organization. My primary goal is to usethe interdisciplinary approach I developed for studying nuclear protein import, in which structural, biochemical, molecular and cellular methods will be used in concert to investigate the key complexes involved in each process and establish interaction interfaces. This information will then be used to define how each function is generated by a precisely orchestrated series of interactions, employing structure-based engineered mutants that alter specificinteractions. These mutants will be used to establish the spatial and temporalpattern of interactions that generate function and so enable these important cellular processes to be understood at the molecular level.

Amount: £535,853
Funder: The Wellcome Trust
Recipient: Medical Research Council

Structural studies on ribosomes. 16 May 2007

Following our determination of the atomic structure of the 30S subunit in 2000, we have recently solved the high resolution structure (2.8 ) of the entire ribosome complexed with its mRNA and tRNA ligands. We propose to determine the structures of the ribosome bound to several ligands and factors. These include release factors RF1 and RF2, which recognize stop codons and release the nascent polypeptide chain; ribosome recycling factor, which is involved in recycling ribosomes to start a new rou nd of translation; the endonuclease relE, which binds to stalled ribosomes and cleaves mRNA; and the complex of the protein SmpB and tmRNA, which is used by bacteria to rescue ribosomes stalled on defective mRNA. We also propose to crystallize complexes of the ribosome in complex with the GTPase factors EF-Tu and EF-G arrested at specific points along the translation pathway. Structures of these complexes will shed light on the mechanisms underlying translation, including the interaction of fac tors with the ribosome and conformational changes during translation. Finally, we shall solve the structures of the eukaryotic small ribosomal subunit in complex with several initiation factors to understand structural changes along the initiation pathway.

Amount: £754,149
Funder: The Wellcome Trust
Recipient: Medical Research Council

Connecting defective replication initiation to inherited human diseases: Biochemical and genetic analysis of the RecQL4 helicase. 01 Nov 2006

We have found that the RecQL4 protein, mutated in human diseases characterizedby chromosome fragility, developmental malformations and premature aging, plays an unexpected role in the initiation of DNA replication (Sangrithi et al. (2005) Cell 121, 887). RecQL4 contains an N-terminal domain homologous to yeast Sld2, and a RecQ-domain, but lacks other features conserved in RecQ helicases. Our first key goal is to determine how RecQL4 promotes assembly of the replication machinery at origins. We find that the Sld2-like domain is phosphorylated by cyclin/CDK activity, and interacts with Cut5/TopBP1, and will investigate the functional effects of phosphorylation on RecQL4 activity and function. In an ongoing collaboration with Shamoo's lab in Houston, a structural analysis of RecQL4 domains is underway, with encouraging preliminary progress. We will perform structure-based analyses of RecQL4 function using this platform. Our second key goal is to develop a vertebrate genetic system to study the functional effects of disease-associated RecQL4 mutations on replication-associated processes like chromatid cohesion that maintain chromosomal integrity. The system will also facilitate genetic analysis of thebiological pathways dependent on RecQL4 activity. Our work should provide insight into the fundamental mechanisms controlling replication initiation, and into how their dysregulation triggers human genetic diseases.

Amount: £164,396
Funder: The Wellcome Trust
Recipient: Medical Research Council

Music From the Worm Farm. 02 Jul 2008

MUSIC FROM THE WORM FARM will be a six-month research and development residency in the Nurrish Lab within MRC Cell Biology Unit, University College London, exploring a new and experimental collaboration between composer Keith Johnson and neurobiologist Stephen Nurrish. The deep questions at the heart of both our interests are those that concern the brain and the body, what we think and what we do, and the mysterious middle ground between them. The residency will be documented and disseminated via a website; including written and visual material alongside original musical works, and a public presentation.

Amount: £13,289
Funder: The Wellcome Trust
Recipient: Medical Research Council

Workshop on new antiretroviral therapy (ART) trials in Africa to be held in Entebbe, Uganda on 29-30 March 2007. 30 Jan 2007

Workshop on new anti-retroviral therapy (ART) trials in Africa Prioritising the main questions about ART treatment strategies now facing Africa needs to be undertaken by professionals at sites treating adults, children and families with HIV infection on the ground in Africa, in particular centres who have already been involved in addressing research questions around current first-line ART. Partnerships between such groups and those from the North in order to build on expertise learnt from managing patients, as well as expertise in the design and execution of large multicentre clinical trials is needed to identify knowledge gaps and opportunities and to drive the agenda forward. A number of questions need answers from large randomised controlled trials. These can be broadly divided into: The timing of ART decisions When to start When to switch from first-line to second-line ART Strategies to maximise long-term efficacy and minimise toxicity. Approaches for both first and second-line ART include cycling drugs and drugs regimens, induction-maintenance approaches, simplification of treatment to improve adherence, and intermittent therapy. Monitoring patients prior to and on ART - with which tests and how frequently Management of patients failing second-line therapy Use of adjunctive therapies with ART - such as immunomodulants, nutritional supplements and drugs for prevention of opportunistic infections.

Amount: £15,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Investigating the early post-entry steps of the retrovirus life cycle. 23 Jun 2008

This research aims to define the poorly understood early post-entry stages of the retroviral lifecycle, in the hope that this will lead to new antiretroviral drug targets, improved gene therapy vectors, and better animal models for HIV/AIDS. Mutagenesis studies have implicated the viral capsid and p12 proteins in the trafficking of MLV particles. Viruses with specific mutations in either of these proteins are unable to accrue their DNA in the cell nucleus. Using a variety of virological assa ys I will determine the function of these proteins and assess whether p12 recruits a cellular factor required for replication, or if p12 blocks a cellular inhibitor of infection. I will also compare the roles of MLV and HIV capsids in viral trafficking. In addition, I will investigate cellular restriction factors that block early post-entry events. I will study the restriction of a novel human gamma-retrovirus, XMRV, recently isolated from prostate cancer patients. Comparing the restriction o f XMRV with other retroviruses will help to define the specificity and mechanism of restriction. Finally, I will identify novel cellular proteins involved in early post-entry processes by analysing the protein complexes of TAP-tagged p12 and Fv1 proteins, and studying the effects of RNaseH on retroviral infection.

Amount: £749,611
Funder: The Wellcome Trust
Recipient: Medical Research Council

Facility costs 16 Sep 2008

Not available

Amount: £400,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Auxiliary factors for microRNA processing. 31 Oct 2007

We have discovered the existence of auxiliary factors for miRNA processing. Here, we will investigate the mechanism by which hnRNP A1 facilitates the Drosha-mediated processing of miR-18a. We will investigate how the abundance of hnRNP A1 correlates with miR-18a expression and influences the regulation of miR-18a mRNA targets. More importantly, these experiments should shed light on what makes a particular miRNA require an auxiliary factor for its processing. We aim to identify other miRNAs that require hnRNP A1 for their processing and to define the generality of RNA-binding proteins as auxiliary factors for miRNA processing.

Amount: £197,449
Funder: The Wellcome Trust
Recipient: Medical Research Council

Investigating functions of the chromosomal protein Ledgf. 10 Jul 2008

We aim to investigate the interactions, functions and targets of the mammalian chromosomal protein PSIP1/LEDGF. This protein has recently attracted attention because of its role in guiding the integration of HIV-1, and other lentiviruses, into preferred sites in the host genome. However, there has been little study of the normal cellular function of this protein. We identified Psip1 as a chromosome-associated protein in a gene-trap screen and the phenotypes that resulted from Psip1 disruption in mutant mice led us to suggest that Psip1 may act in the polycomb pathway of chromatin-mediated gene regulation. Using Psip1 mutant cells and animals, together with antibodies that recognise and immunoprecipitate the different isoforms of Psip1, we propose to investigate the other nuclear proteins that Psip1 interacts with and to test whether Psip1 binds to a specific histone modification. Finally, downstream transcriptional targets of Psip1 will be investigated though expression microarray and real-time RT-PCR comparison of wild-type and mutant cells and by chromatin-immunoprecipitation of Psip1 genomic binding sites. Potential roles of Psip1 in regulating the expression of Hox genes, and genes on the X-chromosome, will be a particular focus.

Amount: £181,679
Funder: The Wellcome Trust
Recipient: Medical Research Council