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Results

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Leeds

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £150,000
Funder: The Wellcome Trust
Recipient: University of St Andrews
Amount: £2,560
Funder: The Wellcome Trust
Recipient: University of Leeds

Sex differences in the brain and behaviour: activational and organisational effects of steroid hormones during puberty. 13 Dec 2005

The aim of this project is to investigate both activational and organisationaleffects of steroid hormones on novelty-seeking behaviour using a rodent model,with particular emphasis on the hormonal changes that accompany puberty. The research will involve manipulating hormone levels during puberty in male and female rats and examining short-term and long-term effects on sex differences in novelty-seeking, using well-established behavioural tests such as the elevated plus-maze and open-field. The proposed research will test the hypothesis that differential exposure to steroid hormones during puberty directs the development of brain and behaviour along male-typical or female-typical pathways by influencing brain development. The dopamine neurotransmitter system is an important brain system that is involved in modulating the rewarding effects of novelty and that undergoes considerable re-organisation during puberty. The effects of pubertal hormone manipulation on the developing dopamine system will be investigated by studying the development of sex differences in novelty-seeking behaviour and also through the administration of psychostimulants, such as d-amphetamine. As the dopaminesystem plays a role in the rewarding effects of drugs of abuse, as well as being involved in novelty-seeking behaviour, this research has implications for our understanding of sex differences in drug addiction in human beings.

Amount: £332,775
Funder: The Wellcome Trust
Recipient: University of St Andrews

Does 2A-mediated stop codon-independent termination of translation predominateover start codon-independent re-initiation of translation under conditions of translational 'stress' ? 19 Oct 2005

The oligopeptide 2A sequence (just 18aa) mediates a co-translational 'cleavage'. When ribosomes encounter 2A, two outcomes ensue. Either (i) translation terminates in a stop codon-independent manner, or, (ii) translation of a specific (glycyl-prolyl) peptide bond is 'skipped' and translation, in effect, re-initiates to synthesis downstream sequences. We propose that this method of protein biogenesis confers the ability to preferntially translate only one part of an open reading frame under conditinos of translational 'stress'. At latter stages of infection this system could direct the remaining cellular resources into translating sequences upstream of 2A (capsid proteins), rather than those downstream (replication proteins). In this manner, the yeild of progeny virions could be enhanced. '2A-like' sequences are found in a very wide range of pathogens and 2A is used extensively in biomedical and biotechnological applications. Our findings will help interpret the role of 2A-like sequences in these other systems and underpin its use in biotechnology. The key goals of the project are twofold; (i) to build a kinetic scheme of protein biogenesis of TME to determine if more capsid, than replication, proteins are made duringinfection, and (ii) to identify what aspect of the translational machinery is determining the outcome of 2A- mediated 'cleavage'.

Amount: £343,140
Funder: The Wellcome Trust
Recipient: University of St Andrews

Do adaptive changes in ECG, in response to voluntary exercise training, reflect changes in myocardial ion channel gene expression and single myocyte electrophysiology? 07 Nov 2005

We wish to understand how exercise benefits the heart. We have a rat model of voluntary exercise that results in cardiac ventricular and myocyte hypertrophyand modification of the electrical properties of single myocytes. These effects are dependant upon the regional origin of the myocytes within the leftventricular wall.We now wish to test whether whole heart electrophysiology andion channel gene expression is altered in a manner consistent with these cellular changes. We will measure the adaptive changes in the ECG at rest and during voluntary exercise in conscious, unrestrained animals using telemetry. Using PCR arrays on the same, isolated hearts we will then identify the ion channel and hypertrophy marker genes that respond to voluntary exercise. This approach will allow us to link levels of activity with adaptive changes in ECG, cardiac growth and gene expression profiles for each individual animal. We will also determine whether these changes are cardioprotective, making the model less prone to arrhythmias. Key goalsi) Linking voluntary exercise-induced changes in whole heart electrophysiology and ion channel gene

Amount: £150,564
Funder: The Wellcome Trust
Recipient: University of Leeds

WATCH IT- a feasibility study of a community intervention to reduce morbidity in obese children. 01 Nov 2005

WATCH IT is a community programme for obese children that aims to influence behaviour in the long-term, and so impact on adult obesity, heart disease and diabetes. This proposal sets out a feasibility study for a multicentre randomised controlled trial of WATCH IT. This research will provide 'proof of concept' as well as answers to important methodological issues that include the feasibility of recruiting children; the acceptability of randomisation to a no-treatment arm; the acceptability of outcome measurements (particularly blood tests and a DEXA scan); the sustainability of participation over a year; an accurate sample size estimate based on the change in body fat. Children will be assigned to the WATCH IT programme or a control non-intervention group for a period of 12 months. The intervention is delivered through the NHS by health trainers in partnership with sports centres. It takes a motivational counselling, solution focused approach along with group physical activity sessions. A formal uncontrolled pilot of the intervention in Leeds shows that it has been successfully implemented in disadvantaged areas, that attendance levels are good and sustained, and that there has been some reduction in adiposity for most children. The clinical outcomes of interest include changes in adiposity, lifestyle, quality of life and metabolic risk.

Amount: £153,062
Funder: The Wellcome Trust
Recipient: University of Leeds

Functions of the hepatitis C virus NS5A protein in viral replication. 25 Oct 2005

Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease. Progress in understanding viral replication has been hampered by the lack of a robust in vitro culture system. We propose to exploit recent developments in our laboratory to analyse the function of the HCV NS5A protein in viral RNA replication. NS5A is a phosphoprotein that is a key component of the viral RNA replication complex, but its precise role remained to be elucidated. Our studies will proceed in two interrelated areas: Firstly, we will use baculovirus vectors capable of delivering replication competent HCV genomes and sub-genomic replicons into hepatocytes, coupled with a mass spectrometry based approach, to unambiguously define the sites of phosphorylation. This will allow us to identify the kinases involved and use this information to assess the role of phosphorylation in RNA replication. Secondly, we have recently introduced a biotin acceptor domain into NS5A in the context of the subgenomic replicon - the resulting constructs are replication competent. We will exploit this advance to purify RNA replication complexes using avidin-affinity chromatography and use proteomic approaches to identify the cellular proteins associated with these complexes.

Amount: £219,276
Funder: The Wellcome Trust
Recipient: University of Leeds

Investigation into a novel mechanism regulating KSHV reactivation. 06 Jul 2006

Kaposi s sarcoma associated herpesvirus virus (KSHV) is the most recently identified human tumour virus. It is the etiological agent of all forms of Kaposi s sarcoma and is also associated with AIDs-related lymproliferative diseases. KSHV has two distinct forms of infection, latent persistence and lytic replication. Although, latent persistence of the KSHV genome has been implicated in tumourigenesis, it is evident that lytic replication plays an important part in the pathogenesis of KSHV infect ion. Therefore, it is essential to study the molecular mechanisms of reactivation and the control of lytic gene expression for a better understanding of KSHV pathogenesis. The KSHV ORF 50 protein is the key transcriptional activating protein which regulates the latent-lytic switch. We have recently demonstrated that KSHV ORF 50 interacts with the cellular protein, Hey-1. This is a particular intriguing interaction, as Hey-1 is a transcriptional repressor protein. Herein, we aim to test the hy pothesis that ORF 50 interacts with Hey-1 to promote its degradation via the ubiquitin proteasome degradation pathway, specifically acting as an ubiquitin E3 ligase. Moreover, we aim to determine the role of Hey-1 in the KSHV latent-lytic switch and whether Hey-1 degradation is required for KSHV lytic replication.

Amount: £190,598
Funder: The Wellcome Trust
Recipient: University of Leeds

Cytosolic phospholipase A2a association with the Golgi apparatus regulates vascular function. 11 Jul 2006

We have discovered that cytosolic phospholipase A2a (cPLA2a) is inactivated byassociation with the Golgi apparatus in confluent monolayers of endothelial cells. This inactive pool of enzyme can be released from the Golgi when the monolayer is wounded. It then can bind to target membranes and lead to prostaglandin synthesis. We want to define the biochemical basis of Golgi association. Our evidence (co-immunoprecipitation, co-localisation, siRNA) points strongly to binding of cPLA2 to annexin A1 and other proteins. We shalldefine peptide sequences responsible for cPLA2 binding to the Golgi apparatus.Such peptides will be tested for their ability to promote release of cPLA2 from the Golgi leading to elevation of prostacyclin levels and thus reduction of blood pressure and clotting.

Amount: £156,624
Funder: The Wellcome Trust
Recipient: University of Leeds

Role of the low-density lipoprotein receptor-related protein in prion protein metabolism. 27 Jun 2006

The prion protein (PrP) is the principal agent responsible for the transmissible spongiform encephalopathies, a group of neurodegenerative diseases including Creutzfeldt-Jakob disease in humans. In these prion diseases the normal cellular form of the prion protein (PrPC) undergoes a conformational change to the protease-resistant, infectious form PrPSc. As the conversion of PrPC to PrPSc occurs at the cell surface or in an endocytic compartment, understanding the mechanisms and molecular partner s involved in the endocytosis of PrPC is central to both the normal cell biology of the protein and to disease pathogenesis. We have preliminary experimental data indicating that the GPI-anchored PrPC is piggy-backed onto the transmembrane low-density lipoprotein receptor-related protein (LRP1) in order to access the clathrin-coated internalisation pathway. We hypothesise that this interaction is critical for the normal cellular metabolism of PrPC and regulates its conversion to PrPSc. The ove rall aim of this proposal is to determine the role of LRP1 in PrP metabolism. The specific objectives are: (1) to characterise further the role of LRP1 in the endocytosis of PrPC; (2) to map the molecular interactions between LRP1 and PrPC; and (3) to determine the role of LRP1 in the conversion of PrPC to PrPSc.

Amount: £187,799
Funder: The Wellcome Trust
Recipient: University of Leeds

The role of antirestriction "DNA mimic" proteins in horizontal gene transfer and the spread of antibiotic resistance. 06 Jul 2006

We propose to carry out a comprehensive genetic, biochemical and structural characterisation of the ardA and ardB antirestriction genes present on many mobile genetic elements residing in bacterial chromosomes as transposons and prophage. We wish to determine whether these Ard proteins are responsible for the extremely effective spread of antibiotic resistance genes also present on these mobile elements. The phenomenon of antirestriction may allow mobile elements to spread throughout bacterial populations despite the fact that the majority of bacteria have multiple and efficient restriction systems which, in the laboratory at least, represent a strong barrier to horizontal transfer. Bioinformatics and preliminary experimental work has identified many candidate ard genes and we will take a structural genomics approach to their analysis utilising high-throughput cloning, expression and crystallisation techniques to maximise our chances of achieving our goals, namely, the genetic, biochemical and structural understanding of at least two representatives of each of the ArdA and ArdB protein families. Of particular interest is the prediction that the Ard proteins may be structural and electrostatic mimics of the DNA recognised and bound by restriction enzymes as recently demonstrated by us for another, unrelated antirestriction protein.

Amount: £38,460
Funder: The Wellcome Trust
Recipient: University of St Andrews

'Re-Visiting the Institution: Fresh Perspectives on the History of Physical Disability' workshop to be held at the University of Leeds on 26th June 2006. 22 May 2006

Meeting: Re-Visiting the Institution: Fresh Perspectives on the History of Physical Disability, Leeds Humanities Research Institute, University of Leeds, 26 June 2006 The role of the institution in the care and education of disabled people has become the subject of controversy. Some of the roots of contemporary disquiet relate to practices and attitudes that have a long history. Other concerns derive from the traditional close nexus between institutions and charitable organizations. Yet historically institutions have occupied a central position in the lives of many generations of disabled people. Indeed their longevity suggests that they have proved flexible, adaptable and of continuing relevance. Many current issues and debates have perplexed and infatuated reformers and activists for centuries. For historians of disability, therefore, there is no escaping the centrality of the institution. Yet, it remains a neglected area of historical research. Physical disability especially has been overlooked by historians. Thus this workshop is needed in order to further our understanding of an issue that is both controversial and topical. Disability history is a new and growing field. The number of academics who research within the area is quite small. Scholars work in isolation at different universities and in different disciplines. There is a need to bring people together in order to promote ties between both academics and institutions and encourage future collaborative research. As disability history is still very much in its nascent stages in the UK, such a workshop will help to promote awareness and interest in the field. By collaborating with the Centre for Disability Studies at the University of Leeds, the workshop will raise the profile of the role of history within disability studies.

Amount: £1,595
Funder: The Wellcome Trust
Recipient: University of Leeds

Transnational migration in SE Asia and the health of children left behind. 16 May 2006

This project will examine health and welfare outcomes, in four South-East Asian countries, for children under 12 years of age left behind when their father and/or mother became a transnational migrant. Primary cross-sectional data will be collected from both migrant and non-migrant households across sampled communities and will include anthropometric measurements, validated health measures (e.g SDQ) and well-being measures. Multivariate techniques (logistic or multinomial regression) will be used to build a series of models incorporating contextual and individual independent variables and designed to test five important hypotheses. In sum, these formalize expectations that the health and well-being of left-behind children is positively associated with father's absence, and (for physical health) with mother's absence under certain conditions, but (for mental health/well-being) negatively associated with mother's absence. Child age and gender and country/local community characteristics are expected to influence outcomes, once other independent variables are taken into account.Selected qualitative interviews will provide in-depth insight into issues raised and aid the interpretation of quantitative findings. Our key goals are to: 1) establish systematic associations between parental absence and child health/well-being; 2) provide a basis for future longitudinal analysis on an under-researched topic; 3) contribute to an evidence base for policy development.

Amount: £196,438
Funder: The Wellcome Trust
Recipient: University of St Andrews

Gating of bacterial transporters and ion channels involved in cellular homeostasis. 17 Oct 2005

We have established that bacterial cells require cellular homeostasis for growth and survival in diverse niches. Ion channels play major roles in cellular homeostasis, as exemplified by our previous work on mechanogated (MscS & MscK) and electrophile-activated (KefC) channels. We have made considerable progress in understanding the gating of these two channel types and the future programme will concentrate specifically on the gating transitions in the channels. Additionally, we will pursue high resolution structures for the closed state of both MscS and MscK and assess important regions of the KefC structure in order to link them to function. The team members have become expert in electrophysiology, molecular genetics and protein biochemistry and they have made significant contributions to understanding the mechanisms and physiological roles of bacterial ion channels. The programme builds on these core skills, which will be augmented by strategic structural and biophysical collaborations (Naismith & Perozo). The key objectives will be: Detailed understanding of the gating transition of the MscS and MscK channels. Closed structures for MscS and MscK. Structural analysis of KefC - definition of the ion translocation pathway and the gating transition.

Amount: £306,142
Funder: The Wellcome Trust
Recipient: University of St Andrews

Molecular biology of bunyavirus host cell interactions. 24 Apr 2006

The Bunyaviridae is a family of mainly arthropod transmitted viruses that contain a tripartite single-stranded RNA genome. Some members of the family are of medical importance causing encephalitis or haemorrhagic fever in man. My laboratory has used Bunyamwera virus, the prototype of the family, as the representative on which to perform molecular biological studies such as functional analyses of recombinant expressed viral proteins, and the development of a reverse genetic system to recover infe ctious virus entirely from cDNAs. This proposal exploits the materials and reagents we have developed to continue and expand our work analysing the replication processes of bunyaviruses at the molecular level, with the overall goal of understanding how the virus interacts with host cells of mammalian and insect origin. Our underlying hypothesis is that differences in virus:cell protein:protein interactions between these cell types determine the outcome of infection. Specifically, using a combina tion of molecular, biochemical and cell biological approaches we will address the following interrelated areas: (i) interactions of viral proteins with cellular proteins during bunyavirus replication; (ii) real-time microscopic analysis of bunyavirus infection using fluorescently tagged viruses; and (iii) functional analysis of the bunyavirus NSs protein in mammalian and insect cells.

Amount: £1,224,645
Funder: The Wellcome Trust
Recipient: University of St Andrews

You and yours: a series of workshops designed to help you understand the science of how your body works. 22 May 2006

"You and Yours" A series of workshops designed to help you understand the science of how your body works The University of Leeds plays an important role in the City of Leeds, its life and culture. Ask members of the public about the University and they will talk readily about our students and the buildings. What frequently remains invisible is the range of scholarly activities that takes place within them and the relevance of these to the day to day lives of the people we seek to serve. "You and Yours" will be a series of six events held on the University campus. Each event will focus on a particular aspect of the body, e.g. "You and Your Heart", and present the latest thinking, research and health approaches being be used, with the aim of demystifying medicine. It is intended that each event will be highly interactive and where possible use a range of media (including drama). All events will have presentations from clinicians, researchers and expert patients. If appropriate, the patient's journey through the health system will be used as a vehicle for illuminating the multitude of ways in which the University (and science) contributes to positive health outcomes in the local community. The University, as part of its commitment to knowledge transfer, has a range of community based activities, e.g., links to schools and local colleges of further education, to support health throughout the curriculum, and we would seek to promote these events specifically to the groups as part of adding value to these partnerships. We are also actively exploring with local media a campaign to run in conjunction with the proposed events to raise public awareness about the topics that we will be covering. As part of our commitment actively to engage patient voices into the work of the University, we would use our existing networks of expert patients and patient teachers to ensure a strong user involvement in the design of all the events.

Amount: £29,998
Funder: The Wellcome Trust
Recipient: University of Leeds

k-t accelerated cardiac magnetic resonance myocardial perfusion imagaing. 06 Dec 2005

Coronary Heart Disease (CHD) remains a major health problem. Cardiac magnetic resonance (CMR) imaging could become one of the most important future ict the diagnostic tools for its assessment. It already provides excellent anatomical information and can assess contractile function and "viability" of the will myocardium with very high spatial resolution. However CMR imaging of myocardial perfusion remains limited by problems of temporo-spatial resolutionand data analysis.In this fellowship I will apply the novel methods k-t BLAST and k-t SENSE, combined with new multi-channel MR receiver coils to perfusion imaging. The aim of this work will be to develop a CMR myocardial perfusion pulse sequence that covers the entire heart with similar spatial resolution ascurrent morphological CMR methods. I will then evaluate these pulse sequences in a series of clinical studies in which CMR data will be compared with invasive measurements of coronary flow. This work will be carried out in collaboration with a leading expert in the analysis of myocardial perfusion data and will include the first systematic evaluation of current methods for the analysis of myocardial

Amount: £545,352
Funder: The Wellcome Trust
Recipient: University of Leeds

Equipment only grant for a MALDI Mass Spectrometer with MS/MS capabilities and associated equipment. 24 Apr 2006

A modern MALDI MS/MS mass spectrometer would underpin a major part of the research at the Centre for Biomolecular Sciences, University of St Andrews, a collaboration between the RAE Grade 5 Schools of Biology and Chemistry. These projects are described in this submission and collaborators forms. There is a strong theme of fighting infection by studying the molecular basis of disease and the identification of novel therapeutic targets. Projects requiring MALDI-TOF MS (MS/MS) include: (i) iden tification of host proteins interacting with viral proteins in adenovirus, bunyavirus, paramyxovirus and picornavirus infections, using immunoprecipitations and TAP-tag type strategies; (ii) investigation of the mode of action of anti-fungal peptides, by examining their synergy using a combined transcriptomics and proteomics approach; (iii) the Scottish Structural Proteomics Facility (SSPF), which is using high throughput gene expression, purification and crystallisation to elucidate the structu res of proteins involved in microbial pathogenesis, biosynthetic pathways and archaeal virus proteins; (iv) investigation of archaeal DNA damage protection, detection and repair mechanisms, by identification of the purified protein complexes involved and proteins whose expression levels change upon exposure to damage agents, and (v) definition of the SUMO and NEDD8 proteomes and quantification of changes in these post-translational modifications upon different stimuli.

Amount: £455,308
Funder: The Wellcome Trust
Recipient: University of St Andrews