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The National Lottery Community Fund (214,189) The Wellcome Trust (16,377) Sport England (15,905) Co-operative Group (12,021) The National Lottery Heritage Fund (10,201) Lloyds Bank Foundation for England and Wales (5,254) Garfield Weston Foundation (4,580) Northern Rock Foundation (4,331) The Henry Smith Charity (4,267) Community Foundation serving Tyne & Wear and Northumberland (4,121) Esmée Fairbairn Foundation (3,470) Woodward Charitable Trust (2,618) Department for Transport (2,577) Paul Hamlyn Foundation (2,022) The Tudor Trust (1,992) Quartet Community Foundation (1,823) Wolfson Foundation (1,817) BBC Children in Need (1,693) The Robertson Trust (1,542) Heart Of England Community Foundation (1,463) County Durham Community Foundation (1,373) Glasgow City Council (1,365) Essex Community Foundation (1,299) London Borough of Southwark (1,260) Community Foundation for Surrey (1,184) Birmingham City Council (1,103) Greater London Authority (1,065) City Bridge Trust (1,018) London Catalyst (1,008) Comic Relief (998) Guy's and St Thomas' Charity (995) Somerset Community Foundation (995) Nesta (914) Corra Foundation (900) Masonic Charitable Foundation (895) Power to Change Trust (870) Oxfordshire Community Foundation (869) Ministry of Justice (774) The Clothworkers Foundation (731) Trafford Housing Trust Social Investment (703) Walcot Foundation (641) Suffolk Community Foundation (620) The Dulverton Trust (603) Barrow Cadbury Trust (591) Scottish Council For Voluntary Organisations (591) Quixote Foundation (560) Devon Community Foundation (537) A B Charitable Trust (526) Two Ridings Community Foundation (510) Sussex Community Foundation (452) See Less

Results

Modelling and functional analysisof the slender to stumpy transition in African trypanosomes. 26 Apr 2006

To generate marker cell lines for the stumpy life stage of Trypanosoma brucei. - To study the dynamics of the slender and stumpy cells during infection. - To use the reporter cell lines for further characterisation of SIF. - To identify regulatory signals for stumpy-specific gene expression. - To further characterise the function of PAD1 and adjacent family members.

Amount: £136,849
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The Cellular and Molecular Basis of Disease. 26 Apr 2006

The molecular details of the processes involved in maintaining the identity of centromeric chromatin are only rudimentary understood, in part because it is currently impossible to specifically manipulate the microenvironment of single centromeres. Employing a novel Human Artificial Chromosome (HAC), we aim to analyse in detail how the epigenetic information at an operative centromere modulates centromere identity and function. This research will provide a crucial contribution to understanding the vital processes of sister chromatid segregation during mitosis, aberrant execution of which can result in birth defects and cancer. The following questions will be addressed: 1. Which histone modifications define a functional centromere? 2. Do these modifications change in the course of the cell cycle, conferring a temporal component to positional information? 3. How do specific histone modifications affect centromere function?

Amount: £136,849
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Molecular Dissection of CCCH ZFPs - Gatekeepers of the African Trypanosome Genome. 26 Apr 2006

This project aims to investigate the roles of the Trypanosoma brucei CCCH zinc finger proteins (CCCH ZFP) as novel regulators of gene expression. The ultimate goal is to understand the unusual mechanisms utilised by trypanosomas to regulate gene expression and use these as fundamental targets for anti-parasitic drugs. Specifically this proposed research will: i) Define if two CCCH ZFPs (denoted TbC3H43.7/49.6) are essential for controlling T.brucei lifecycle progression and the contribution of the CCCH motifs within TbC3H43.7/49.6 as functional determinants for trypanosome cellular development. ii) Determine if there is a functional relationship in cell development between TbC3H43.7/49.6 and any phosphorylation-dependent protein pathways. iii) Identify the RNA binding capacity and specific RNA targets of TbC3H43.7/49.6 as the putative mechanism of post-translational control of gene expression. iv) Analyse the specific targets of TbC3H43.7/49.6 for their role in differentiation using established assays (over-expression or RNAi) on transgenic parasites generated in BS cells. v) Use a CAT reporter system to define any interacting RNA sequences governing mRNA stability.

Amount: £141,902
Funder: The Wellcome Trust
Recipient: Imperial College London

Intracellular dynamics of the influenza A virus RNA polymerase and their role in influencing virus host range. 26 Apr 2006

WT Studentship for Ms Agnes Foglein : 4-year PhD studentship in Infection and Immunity. Influenza A virus has a segmented, negative stranded RNA genome. In order to replicate in an infected cell it has to transcribe this genomic vRNA into mRNA (for viral protein expression) and into cRNA; an exact copy that serves as a template for amplification of the genome for new viral particles. To achieve this, influenza virus encodes a viral RNA dependent RNA polymerase. This complex, consisting of 3 proteins - PA, PB1 and PB2 -transcribes all the three RNA species required by the virus: mRNA, cRNA and vRNA. However, to achieve this it needs to interact with the cellular transcription machinery to "steal" the cap of cellular mRNA and use it for viral mRNA. There is much evidence that the viral polymerase genes are a major determinant of host range and pathogenicity. Although all three viral polymerase subunits play an important role and the combination of these also has an influence, PB2 is especially important for host specificity. The amino acid at position 627 seems to be a "signature" for the virus, with avian strains preferentially displaying glutamic acid (Glu) and human strains lysine (Lys). Change from Glu627 to Lys induces severe pathogenicity and increased replication of avian virus in mice. As Shinya et al. show, the single amino acid substitution converts a nonlethal H5N1 virus isolated from man to a lethal virus in mice. However, the molecular mechanisms behind this host range determination are unclear. While cell tropism did not seem to be influenced by the variant of PB2 in a mouse model, the human variant showed accelerated viral spread in infected animals and higher virus titers were measure in cell culture models (Shinya et al. 2004). The aim of the project is to investigate what molecular mechanism lies behind the species specificity conferred by PB2.

Amount: £141,232
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mitochondrial probes for oxidative stress. 08 Feb 2006

Mitochondrial probes for oxidative stress Interest has recently been focused on the damage caused to mitochondria by reactive oxygen species (ROS) such as hydroxyl (HO·), peroxyl (HO2·) and superoxide (O2·) radicals. Such damage appears to be causal in the universally experienced, but poorly understood, process of ageing. Thus, the extension of lifespan when there is calorie restriction in the diet of rats appears to arise at least in part from reduced oxidative damage to mitochondria. Furthermore, murine life span can be extended by overexpression of catalase targeted to mitochondria, where the increased removal of hydrogen peroxide will reduce ROS production and consequent damage. Oxidative stress is also important in a range of pathologies including the accelerated atherosclerosis associated with diabetes. Mitochondria are particularly susceptible to oxidative stress because much of the intracellular production of ROS arises in these organelles, particularly when a large proton motive force is generated by mitochondria respiring, but not producing ATP. Understanding the role and significance of ROS generated in mitochondria in ageing and pathologies where oxidative stress appears important has been hampered by a lack of mitochondria-targeted probes that specifically detect radicals. The aim of this research is to develop such generally useful probes and to use them to test the hypothesis that increased production of ROS in mitochondria is a major contributor to oxidative damage during hyperglycaemia (important in diabetes). The only technique that observes radicals directly and to the exclusion of all non-radical species is electron paramagnetic spectroscopy (EPR). The technique is very versatile and is useful in studies extending from simple chemical reactions in the test tube to the observation of radicals in vivo. Thus, the probes to be developed are for use with EPR spectroscopy. The specific objectives are to: (i) Design and synthesise new hydroxylamine H-atom transfer probes for EPR spectroscopy. (ii) Characterisation of their chemical reactivity with radicals and the longevity of the EPR signal produced in the presence of ascorbic acid. (iii) Determination of uptake into isolated mitochondria and whole cells. (iv) Application of probes to investigate the role of mitochondrial dysfunction in oxidative damage in hyperglycaemia (and to protect cells against cellular ageing).

Amount: £2,060
Funder: The Wellcome Trust
Recipient: University of Glasgow

Stimulus-timing-dependent plasticity in the auditory cortex. 14 Dec 2005

Stimulus-timing-dependent plasticity in ferret auditory cortex Adult cortical circuits possess considerable plasticity, which can be induced by modifying their inputs. In the visual system, repetitive pairing of stimuli of different orientations or at different spatial locations leads to changes in the receptive field properties of cortical neurons and in human perception, the nature of which depends on the temporal order and interval between the pairs of stimuli. The aim of this project is to determine whether stimulus-timing-dependent plasticity (STDP) is also present in auditory cortex. We will investigate whether the sensitivity of ferret cortical neurons to the location or pitch of a stimulus can be altered by asynchronous auditory conditioning, and whether the degree of plasticity varies from one cortical area to another and therefore with the role of neurons in processing the stimulus attribute in question. Another aim is to study the effects of pairing visual and auditory stimuli on the properties of auditory and multi-sensory neurons in this region of cortex, in order to determine whether STDP extends across different sensory modalities. Finally, we will use a similar paradigm to examine the role of multi-sensory experience in mediating training-induced plasticity of auditory localisation in adult ferrets.

Amount: £31,267
Funder: The Wellcome Trust
Recipient: University of Oxford

Chelating recombinant antibodies (CRAbs) against bacterial toxins. 08 Feb 2006

Inhibitors of cGMP-specific phosphodiesterase (PDE5) may be useful for the treatment of cardiovascular diseases such as hypertension. A screen sequence for inhibitors of PDE5 (PDE5i) uses rat models for in vitro and in vivo potency determinations. In order to support their use, the kinetic characteristics and inhibitor sensitivities of human and rat PDE5 were compared. PDE5 was prepared from human and rat platelet cytosol using anion exchange chromatography and enzyme activity determined by monitoring the conversion of [3H]-cGMP to [3H]-5'GMP using scintillation proximity assay. PDE5 was characterised based on substrate specificity, PDE5i sensitivity to UK-343664 and Km for cGMP. The mean apparent Km values (µM), with 95% C.I. (µM), for human pde5 and 4 batches of rat pde5 were 0.54 (0.51, 0.57), 3.1 (1.7, 4.6), 1.7 (0.8, 2.6), 0.8 (0.58, 1.0) and (1.9 (1.1, 2.7) respectively. Rat PDE5 Km values were significantly higher than human PDE5 Km values (P0.1) that might confound interpretation of functional data obtained using rat models in the PDE5i screen sequence.

Amount: £13,835
Funder: The Wellcome Trust
Recipient: Imperial College London

Regulation of tissue inhibitors of matrix metalloproteases (TIMPs) expression in the gastric epithelium. 20 Sep 2006

The aim of this project is to define the mechanisms by which H.pylori infection increases expression of tissue inhibitors of matrix metalloproteases (TIMPs) in gastric mucosal cells, and to determine the consequences for the mucosal remodelling that occurs with infection. The experimental plan is based on our capacity to culture human primary gastric epithelial cells and myofibroblasts transfected with promoter-reporter constructs, to study Helicobacter responses in mice (and determine if they are an useful model) and to identify putative substrates using 2-DG cells and mass spectrometry of selected spots (5,6,7).

Amount: £6,396
Funder: The Wellcome Trust
Recipient: University of Liverpool

The role of glucocorticoid receptor in body composition. 14 Dec 2005

The role of glucocorticoid receptor in body composition 1. To generate a line of GR+/- mice from an existing embryonic stem (ES) cell line and phenotype mice with respect to tissue glucocorticoid sensitivity, HPA axis regulation, susceptibility to dietary-induced obesity (DIO) and body fat distribution. 2. To determine key parameters of glucocorticoid action (GR and 11ßHSD1) in metabolically important tissues (liver, adipose, brain) and their role in body fat distribution in POMC-deficient mice, an established model of HPA hypoactivity which also show hyperphagic obesity on a high fat diet. 3. To determine if GR heterozygosity affects the degree and distribution of obesity induced by HF feeding in POMC+/- mice.

Amount: £39,144
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The Endurance of the Carrier Narrative: 'Patient Zero', Gaetan Dugas, and the Assignment of Blame in Epidemics. 14 Jun 2006

The proposed research intends to establish the origins of the 'patient zero' concept, account for the means of its rapid cultural diffusion, and locate it within a wider historical framework. The project has four key goals. First, it aims to reconstruct the events culminating in the early 1980s epidemiological cluster study that first posited the significance of a 'patient zero'. Second, the extent to which key players, including public health officials, Randy Shilts, the news media, and the entertainment industry, were each responsible for the promotion of the 'patient zero' character will be determined. Third, efforts will be made to reconstruct Gaetan Dugas's experience as a patient, from archival research and interviews with his acquaintances, his doctors, and the public health officials who met with him. Finally, the project aims to demonstrate the cyclical nature of the 'healthy carrier' narrative underlying the 'patient zero' concept. In this regard, the project will consider the treatment, by both the media and public health officials, of Gaetan Dugas in relation to that of 'Typhoid' Mary Mallon. Newly released testimonies from the Krever Inquiry into the contamination of the Canadian blood industry will also be examined as a more recent recurrence of the narrative.

Amount: £79,234
Funder: The Wellcome Trust
Recipient: University of Oxford

The social value of research: concept and practice in Kenya. 08 Jun 2006

A systematic review of the bioethics, social science, regulatory and other relevant literature will describe and analyse the use of the concepts of 'benefit sharing', 'social value' and the 'moral obligations of researchers' in developing country research. In the light of this analysis, using Kenya as a case study, the perceptions and beliefs of key informants (researchers, policy-makers and research governance bodies) will be explored using interviews and other qualitative research techniques. A specific focus of the interviews and subsequent analysis will be the exploration of informants' views about the allocation of responsibility for ensuring that the benefits of research are shared appropriately. This qualitative research will be complemented by an analysis of current practices concerning benefit sharing in Kenya. The research will lead to a report including: an investigation of the role of the concept of 'social value' in the ethics of research in developing countries using Kenya as a case study; analysis of empirical evidence about current benefit-sharing practice and the views of key stakeholders about best practice; a number of recommendations for good practice, and a practical 'social value template' for use by those involved in research in developing countries: funders, policy-makers, researchers and local ethics committees.

Amount: £146,576
Funder: The Wellcome Trust
Recipient: University of Oxford

China stem cell research policy and related ethical issues. 08 Jun 2006

China Stem Cell Research Policy and Related Ethical Issues As stem cell technology continues to expand in its range of clinical uses, a number of moral, technical, ethical and regulatory issues gain importance. These issues are international, national and also local. The proposed study investigates emerging ethical and regulatory tissues in the context of Chinese stem cell science. China is now a rising power in bio-science field. Yet, so far there has been no legislation, and only two ethical guidelines in China to regulate current stem cell research. However, China has realised the importance of an efficient regulation system to balance the scientific and social benefits and resolve the conflicts. The ethical importance of stem cells research thus poses a specific challenge. By visiting stem cell laboratories, stem cell banks, clinics and hospitals, and through interviews with medical researchers, bioethicists and patients, this research will define the core moral and ethical issues at stake in China's context, and give suggestions of applying ethical protocols governing the future regulation of its own stem cell research community. The feedbacks will be sought continually throughout the project from the collaborating investigators. This research will also contribute to the future comparative governance and regulation of human stem cell research and presents implications on universal regulatory guidance.

Malaria burden and control at national, regional and global scales. 22 Jun 2006

The work in this application will provide the most complete understanding of the spatial distributions of malaria risk at national, continental and global scales since the 1960's. The approach will allow for a transparent, evidence-driven estimation of the public health burden posed by the malaria parasite and its diversity in space and time. The epidemiological platform will provide the means to articulate needs and model the impact of changing demographics, climate, poverty and intervention between 2005 and 2030. Effective control, however, will be predicated on a number of operational constraints which must be defined and understood to ensure that patients and communities most in need have access to interventions that work. How well interventions are delivered at national scales is the subject of a complementary programme of research: providing the link between the theoretical impacts of disease control and the likely operational efficiency of interventions when delivered as part of national policies in Africa.

Amount: £3,416,292
Funder: The Wellcome Trust
Recipient: University of Oxford

Transdiagnostic cognitive behaviour therapy for eating disorders: efficacy and mechanisms of action. 22 Jun 2006

Clinical eating disorders such as anorexia nervosa and bulimia nervosa are a cause of substantial physical and psychosocial morbidity. They typically begin in adolescence and often run a chronic course. They are difficult to treat and they impose a significant burden on health services. This application is for funds to continue a long-term, Trust-funded, programme of research on these disorders and their treatment. One major outcome of this research has been the development of the leading evidence-based treatment for eating disorders (cognitive behaviour therapy for bulimia nervosa), a treatment strongly endorsed by NICE and other national clinical practice guidelines. Recently we have developed an "enhanced" theory-driven form of this treatment (CBT-E) that is designed to be suitable for the full range of eating disorders seen in clinical practice, rather than just cases of bulimia nervosa. Our data suggest that CBT-E is a potent treatment for the majority of these patients. We now propose to study: 1) whether CBT-E operates through mechanisms that are specific to it; 2) whether CBT-E is clinically superior to the leading potential alternative treatment; 3) how CBT-E is likely to work; 4) the utility of CBT-E in treating those patients who are severely underweight.

Amount: £3,974,171
Funder: The Wellcome Trust
Recipient: University of Oxford

The placenta, oxidative stress and the maternal inflammatory response in pre-eclampsia. 03 May 2006

This program develops our long-standing research into the pathophysiology of the specific pregnancy disorder, pre-eclampsia. We have proposed that the maternal syndrome arises from a dysfunctional systemic inflammatory response, involving the entire inflammatory network, including endothelium. There are three stages: the response of the specific placental cell, trophoblast, and its mitochondria to the oxidative stress that is a fundamental problem in pre-eclampsia; release into the maternal circulation of trophoblast-derived microparticles and other factors, which signal to maternal endothelium and circulating inflammatory cells; and the triggering of maternal inflammatory responses. We will investigate mechanisms involved in all stages, relating to:i) the importance of lipid rafts and caveolin-1 to syncytiotrophoblast mitochondrial integrity and resistance to oxidative stress; ii) the contribution of apoptosis and necrosis to syncytiotrophoblast microparticle release, both physiological and pathological; iii) the importance of microparticle shedding as a signal to maternal endothelial and immune cells and iv) the potential role of NKT cells in determining the systemic inflammatory responses to processed microparticulate syncytiotrophoblast antigens in normal and pre-eclamptic pregnancies. We seek a more complete understanding of the placental causes of complexities of end-stage pre-eclampsia. The ultimate aim is to facilitate the development of scientifically targeted therapies.

Amount: £1,110,722
Funder: The Wellcome Trust
Recipient: University of Oxford

Assembly, architecture and recognition of bacterial adhesion and invasion complexes. 06 Jul 2006

Novel adhesion complexes (adhesins) from pathogenic bacteria play fundamental roles in colonising the host and propagating infection. Pathogenic bacteria express a variety of surface adhesions that often comprise polymeric structures that forming either filaments or amorphous sheaths. We propose to combine multi-disciplinary structural methods in order to gain a detailed understanding of three model filamentous, multimeric complexes: 1) The Afa/Dr family from pathogenic Escherichia coli, which are associated with both diarrhoeal and urinary tract infections. 2) Bundle forming pili (BFP), which are essential for localized adherence to epithelial cells, auto-aggregation and the full virulence of enteropathogenic E. coli. 3) The Fimbriae associated protein (Fap) from oral pathogen Streptococcus parasanguis, which is responsible for colonization of the oral cavity and formation of biofilms. We will propose functional models that will be tested independently with mutagenesis-driven function experiments.

Amount: £850,023
Funder: The Wellcome Trust
Recipient: Imperial College London

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

TwinsUK Genetic Epidemiology Resource. 16 May 2006

This project aims to build on the existing TwinsUK resource. The currently held Wellcome FGI has funded development of the twin resource and the creation of a website and open access by researchers to limited twin data. We plan to ensure that the resource is investigated as thoroughly as possible, answering specific questions in a variety of fields, using well-designed studies in a cost-effective manner. In addition to maintaining and studying the existing phenotypes we plan: - Collection of new and longitudinal phenotypes eg. Adipose tissue, eye data, inflammatory markers - Linkage Study and statistical analysis on 2,500 pairs - Maintenance and consolidation of twin resource - Extending the use of the database and website development Key goals include: 1.Maintenance and consolidation of the twin resource by ensuring that the biological samples and phenotype databases are safely stored and available for widespread use; to retain motivation of the cohort through regular contact. 2. Make greater use of the resource by strengthening current relationships and forging new links with scientific collaborators and providing controlled access to the full genotypic information and selected phenotypes via the internet. 3. Extend the scientific utility of the resource by collecting new questionnaire data and biological samples.

Amount: £1,063,464
Funder: The Wellcome Trust
Recipient: King's College London

The X11 adaptor proteins and Alzheimer's disease. 27 Feb 2006

Work from our and a number of other laboratories has demonstrated that X11a an d X11b inhibit APP processing and Ab production. However, the molecular mechan isms that underlie this effect are not known. This project is to gain insight into these mechanisms. Release of Ab from APP involves proteases termed secret ases and one key goal of this project is to determine whether theX11s influenc e secretase function. A second key goal is to determine whether X11 inhibition of Ab production involves altered trafficking of APP and/or APPsecretases. Fi nally, we have found that the X11s are involved in neuronal copper metabolism and that one of the secretases (BACE1) is a copper binding protein. Disruption to copper homeostasis is believed to contribute to Alzheimer's disease. The f inal goal is to understand further how copper is delivered to BACE1 and whethe r it influences BACE1 function and Ab production.

Amount: £918,022
Funder: The Wellcome Trust
Recipient: King's College London