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University of Cambridge

Results

Core support for Wellcome Trust/Cancer Research UK Gurdon Instiute. Award for years 4 and 5. 20 Sep 2006

This application requests the continuation of core support to the Wellcome Trust/Cancer Research UK Gurdon Institute. The aim of the Institute, an integrated part of Cambridge University, is to contribute to an understanding of normal animal development, including the processes of cell differentiation, morphogenesis and cell proliferation, and to explain how, should these processes fail, cancers may arise. The Institute attempts to achieve these objectives by recruiting the best scientists and by ensuring that they have the best possible environment for their work. Recruitment is carried out by a committee of Group Leaders, with the main criterion for appointment being scientific excellence. This application is concerned with providing the best scientific environment for our researchers, and indeed the Institute's core support is one of its most important assets, allowing our scientists to spend as much time as possible on their work. This support provides practical assistance, such as media preparation, and secretarial and administrative assistance, including help with grant applications and equipment procurement. It also provides computer staff and a bioinformatician, as well as expertise in confocal microscopy. Core support is essential if the Institute is to maintain its position as a leading centre of cell, molecular and developmental biology.

Amount: £3,005,149
Funder: The Wellcome Trust
Recipient: University of Cambridge

WELLCOME TRUST CENTRE FOR STEM CELL RESEARCH 20 Sep 2006

The new Institute for Stem Cell Biology in Cambridge will be an international centre of excellence in fundamental stem cell research. The Institute will focus on definition of the genetic and biochemical mechanisms that control stem cell fate, providing foundations for applications in disease modelling, drug discovery and regenerative medicine. This proposal is for provision of core resources for embryonic stem cell manipulation and transgenesis. A central resource of skilled personnel will maximise research productivity and continuity, promote cooperation and synergy, and accelerate technological innovation. Timely and efficient production of customised gene-modified stem cells and mice is essential underpinning. Specialised expertise will support advanced genetic engineering of mouse and human stem cells, and operation of robotic platforms to develop screening methodologies for isolating genetic, protein and chemical regulators. A dedicated PdD programme in stem cell biology will capitalise on the opportunity for high level research training provided by the intellectual environment and core facilities in the Institute. A Strategic Award will immediately establish the Institute for Stem Cell Biology amongst the best-resourced and most attractive environments for stem cell research world-wide, providing a magnet for recruitment, and a much-needed focus for UK and European stem cell biology.

Amount: £6,956,531
Funder: The Wellcome Trust
Recipient: University of Cambridge

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fragment-based approaches to the design of candidate drugs that interrupt protein-protein interactions involved in cell regulation. 28 Apr 2006

Structure base drug design and Structural bioinformatics are emerging areas that could help lead drug discovery. The Trust has recently awarded £1,022,854 to Professo'r Sir Tom Blundell and colleagues at University of Cambridge to identify candidate ligands that may advance cancer therapeutics. The applicants plan to extend fragment-based approaches and design novel candidates that interrupt protein-protein interactions exploiting small pockets in protein-protein interfaces, particularly where one component is :a flexible polypeptide that assembles to give a specific structure only in the multiproteiri complex. They are specifically examining the multiprotein complex of human recombinase, Rad51, and the product of the breast cancer associated gene, BRCA2. The applicants plan to screen using X-ray, NMR, mass spectrometry, and other biophysical approaches, together with biochemical and biological assays to select and validate useful ligands. This project could identify drugs that block the BRCA2-RAD51 interaction to sensitise canc~r cells to radiation, DNA cross-linking agents or replication inhibitors, or to directly induce cancer cell death during proliferation. In addition, this project has the potential to validate that protein protein interactions are potentially druggable

Amount: £1,022,854
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £213,508
Funder: The Wellcome Trust
Recipient: University of Cambridge

Collaborations between developing and developed countries in advancing biomedical population genetics, neglected diseases and bioprospecting R&D: developing policy and practice guidelines for going forward in 21st century. 22 May 2006

Studentship in Biomedical Ethics Project title: Collaborations between developing and developed countries in advancing biomedical population genetics, neglected diseases and bioprospecting R&D: Developing Policy and Practice Guidelines for Going Forward in the 21st century. The project will examine the structure, organisation and interplay of key ethical, socio-economic, health-policy and commercial concerns regarding the establishment of sustainable support systems (policies, institutions, R&D and commercial practices) for biomedical collaborations between developing and developed countries, framed around a need to align participant incentives- within a system that promotes and ensures ethical practice. It will elucidate the benefits and shortcomings of current practice; investigate the interplay between trade-offs and competing tensions facing collaborative efforts (e.g. exploration versus exploitation, short vs long-termism, trust vs vigilance, competition vs cooperation, opportunism vs altruism, planning vs emergence); highlight implications; and draw novel collaboration performance measures and improved guidelines for addressing a series of collaboration -specific issues in a multidisciplinary and integrated manner. These include access to genetic resources, benefit sharing and ethical concerns, IPR protection, technology transfer and capacity building in developing countries. Research will build on theoretical and empirical evidence from the fields of global health, bioethics, alliance theory, innovation management and development studies. The project will employ a multiple methodology approach, combining evidence from comparative case studies of collaborative R&D efforts at biomedical centres in the developing world (e.g. at sponsor institutions: Africa Centre for Health and Population Studies and Wellcome Trust's South East Asia Overseas Unit), interview data, company profiles, descriptive statistics, bibliometric and patent data. Empirical evidence for best-practice transfer will draw on contextual insight from the fields of population genetics, neglected diseases and bioprospecting. Such theoretical and practical advancements are pivotal towards spring-boarding cross-national collaboration practice in the biomedical sector, and ensuring that both "First" and "Third World" parties offer each other better credibility, stronger contributions and more equitable benefit distributions in turn.

Amount: £8,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fundamental associative learning processes in psychosis: combined behavioural, functional neuroimaging and psychopharmacological studies. 05 Jun 2006

Delusions are core symptoms of psychotic illnesses such as schizophrenia. Central to our understanding of delusions is the idea that they emerge from a background of abnormal formation of associations. Over the last decade, there has been an increasing understanding of the neuroscience of association formation. This work has emphasised prediction error signal as a drive to associative learning and a guide to allocation of attention and to selection of action. The goal of my proposed work is to test the hypothesis that delusional beliefs arise from changes in association formation as a consequence of abnormal prediction error signalling. In order to do so, I wish to combine behavioural, psychopharmacological and functional neuroimaging studies to:(i) Refine understanding of prediction error-driven associative learning processes in humans(ii) Establish the extent and nature of disruption of these processes, (both in terms of behaviour and brain response) a) in deluded individuals and b) under ketamine administration.(iii) Test directly the possibility of a link between symptoms of psychosis and disturbances in associative learning by evaluating the extent to which these behavioural and brain responses predict the existence or emergence of delusional beliefs (under ketamine and in psychosis).

Amount: £1,028,769
Funder: The Wellcome Trust
Recipient: University of Cambridge

Therapeutic approaches for codon reiteration diseases 05 Jun 2006

I aim to develop therapeutic strategies for diseases associated with protein misfolding and intracellular aggregation, focussing on Huntington's disease (HD) and oculopharyngeal muscular dystrophy (OPMD). First, I will develop our findings that levels of mutant huntingtin fragments can be reduced by inducing autophagy. This strategy attenuates toxicity of the HD mutation in transgenic cell, fly and mouse models. Recent work in cell and fly models suggests that autophagy induction is beneficial for a much broader range of targets, including polyglutamine expansions underlying many spinocerebellar ataxias, and tau. Currently, the only autophagy-inducing drug that is known to reduce mutant huntingtin levels effectively in mammalian brains is rapamycin. While it is designed for long-term use, it has significant side-effects. My aims in the context of this component of the proposal are:1. Further the understanding of the machinery and regulation of mammalian autophagy to aid discovery of safer and more specific targets.2. Test autophagy upregulation as a therapeutic strategy for SCA3 and tauopathies in mouse models. Second, I will exploit our OPMD mouse model for testing 4 known safe drugs/compounds in vivo, on the basis of pilot data showing that they reduce aggregation and toxicity in OPMD cell models.

Amount: £1,645,643
Funder: The Wellcome Trust
Recipient: University of Cambridge

Multidisciplinary studies of the folding of structurally related proteins: how sequence variation affects protein folding, stability, mechanics and disease. 01 Jun 2006

The central theme of this proposal is to investigate the relationship between protein sequence, folding, function and disease at the molecular level. We use a powerful multidisciplinary approach combining biophysical, protein engineering, structural, computational and bioinformatics techniques. Four closely related areas of research are described:Core Studies: The Folding of Related Proteins. How far can we explain (or predict) differences within and between families? We will investigate the relative importance of sequence, secondary structure, topology and chain connectivity.Studies of Multidomain ProteinsOver 75% of human proteins have more than one domain. We will investigate how the folding of one domain is affected by its neighbours and how misfolding is avoided.Mutations and Disease.Most pathogenic mutations are thought to affect protein stability. We will investigate pathogenic mutationsin all-a proteins to see how far it is possible to predict these effects from model proteins. We will compare pathogenic mutations and SNPs on a quantitative basis.Molecular Basis of Protein ElasticityIf a protein is to remain active in the presence of an external force it has to remain folded. How this is achieved will be investigated by combining atomic force microscopy, protein engineering and simulation.

Amount: £1,319,905
Funder: The Wellcome Trust
Recipient: University of Cambridge

Early cell fate decisions and cell positioning in the mouse embryo. 01 Jun 2006

I propose three complementary approaches to study how early events can help to specify polarity of the mouse embryo. I first propose to study developmental cues in the egg whose animal-vegetal polarity dictates one axis of the future blastocyst, and the position of sperm entry determines the second axis. The sperm entry position sets the first cleavage plane and conveys a division advantage upon the cell inheriting it. I will investigate the cytoplasmic events underlying these two consequences of sperm entry and test their relative importance in establishing the embryonic abembryonic polarity of the blastocyst. I also propose to study why, although the animal pole of the egg can be removed without affecting development, its duplication is inhibitory. Secondly I will combine lineage tracing and transplantation studies to ask how polarity of the blastocyst, set up by the above processes, is transformed to give organised signalling centres in the postimplantation embryo. My focus will be to discover the origins of visceral endoderm with potential to signal to the epiblast of the egg cylinder. To determine when such signalling centres become active, I will first concentrate on transplantation experiments that test the ability of anterior visceral endoderm precursors to repress posterior gene activity. The extent of such experiments could be broadened by better knowledge of the patterns of gene expression from the blastocyst onwards. The third part of my proposal aims to identify genes that are expressed asymmetrically along axes of the blastocyst and/or at the earliest times within postimplantation signalling centres or their progenitors. My attention will centre upon finding genes that are differentially expressed in the animal and vegetal halves of the blastocyst or become uniquely expressed in progenitors of anterior visceral endoderm. These will be identified through the construction of subtractive cDNA libraries and by screening microarrays. I will select genes with expression patterns likely to be meaningful in the development of signalling centres and examine the consequences of both their ectopic expression and loss of expression using dsRNAi. In the longer term I propose to analyse how the patterns of expression of these or other genes are rebuilt following perturbation of development. Thus not only do I hope my work wil contribute to a molecular understanding of how asymmetries are established and transmitted to later stages of the embryo in normal development, but also will provide insight into the remarkable regulative properties of the mammalian embryo.

Amount: £2,417,906
Funder: The Wellcome Trust
Recipient: University of Cambridge

Effect of neutrophil priming and de-priming on neutrophil retention in the lung. 06 Dec 2005

Neutrophils become 'primed' after exposure to inflammatory mediators and this greatly enhances their subsequent secretory activity. Priming also alters neutrophil shape/deformability, integrin expression and longevity and hence has a profound affect on their rheological, adhesive and survival properties. Priming is a prerequisite for neutrophil-mediated tissue injury and plays a fundamental role in the pathogenesis of ARDS. Since priming is reversible, I will test whether the pulmonary capillary bed and/or spleen can trap and de-prime systemically-primed neutrophils before releasing them back into the circulation, and whether failure of this function results in neutrophil-mediated lung injury.Specifically, I will address:(i) What is the bio-distribution, preferential disposal site and circulating half-life of primed versus un-primed neutrophils? This will be addressed using 99mTc and 111In-labelled primed/un-primed neutrophils in healthy volunteers.(ii) Can pulmonary capillaries or the spleen retain circulating primed neutrophils, de-prime them and return them to the circulation? I will determine the capacity for neutrophils primed in vivo to de-prime ex-vivo and use flow-based techniques to track the intravascular fate of permanently or transiently primed 111In-labelled cells.(iii) What is the effect of lung vascular (ARDS) and airspace (pneumonia) inflammation on transpulmonary primed neutrophil gradients and does neutrophil transit time and pulmonary retention fraction predict the evolution of ARDS.

Amount: £235,646
Funder: The Wellcome Trust
Recipient: University of Cambridge

Inflammatory bowel disease genetics: candidate gene investigation by genetic association study and expression analysis in ulcerative colitis and Crohn's disease. 06 Dec 2005

Introduction: Inflammatory Bowel Disease (IBD) genetics is an area of rapid scientific progress. Crohn's disease (CD) and ulcerative colitis (UC) comprisethe main and related forms of IBD. Fine mapping of IBD linkage intervals has identified NOD2/CARD15 as a confirmed CD gene, and OCTN1, DLG5 and MDR1 have been recently implicated for CD, UC or both. Several additional strong linkages await resolution, with the prospect of fundamental advance in our understanding of IBD pathogenesis and the heterogeneity within CD and UC.Aim: Working with the world-class facilities and expertise in Cambridge, I aim to perform a systematic large-scale positional candidate gene association study to identify UC and CD susceptibility genes and phenotype-genotype correlations. I will then investigate expression patterns for genes implicatedin the association analysis in intestinal biopsies.Method: Using DNA and clinical data from 2000 UC subjects, I will genotype 768 non-synonymous or tagsingle nucleotide polymorphisms within two strong and replicated regions of linkage. I will then analyse genotypes to identify associated variants, as well as gene-gene and phenotype-genotype correlations. I will also perform replication analyses in an independent panel for CD-associated loci from the UK-wide 500 000 marker Welcome Trust Case Control Consortium study (WTCCC) forwhich the Cambridge group is playing a leading role.Expression patterns of genes identified for both UC and CD will be assessed using quantitative rtPCR,immunohistochemistry and RNA FISH in intestinal biopsies from cases and controls.

Amount: £164,457
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of human herpesvirus 8 K5 gene product in the pathogenesis of pulmonary arterial hypertension. 03 Apr 2006

Identification of heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) in familial pulmonary arterial hypertension (PAH) is a major advance in understanding this condition. Our laboratory, and others, has demonstrated that a reduction in BMP receptor signalling is a feature common to many forms of PAH, even in the absence of identifiable mutations in the BMPR2 gene. Thus, factors that reduceBMP receptor expression or function may be critical to PAH pathogenesis. Recently human herpersvirus-8 (HHV-8) was identified in the pulmonary vasculature of 60% of cases of idiopathic PAH. Like other herpesviruses HHV-8 expresses immunoevasion genes. We (PJL) have shown that the HHV-8 encoded K3 and K5 genes ubiquitinate endogenous immunoreceptors, targeting them for endolysosomal degradation. Our preliminary data shows that K5 interferes with cell surface expression of BMP receptors. This is the first demonstration of aherpesvirus gene product subverting growth factor receptor expression. The original hypothesis underpinning these studies is that ubiquitination and

Amount: £183,726
Funder: The Wellcome Trust
Recipient: University of Cambridge

'What's in a name? - Authorship and Authority in the Transmission of Medicinal Recipes from 'Hippocrates' to 'Galen'. 10 Nov 2005

Names (real authorial names or pseudonyms) attached to ancient pharmacological treatises, or within a treatise, to individual recipes, conferred authority on pharmacological material. This project will investigate the relation between authorship and authority in the transmission of pharmacological knowledge in antiquity, taking into account variations through time, variations according to the literary genres in which recipes are listed, and variations according to the social origin of the authority named. I will study Greek and Latin sources from the second half of the fifth century BC (approximate date of the recipes preserved in the Hippocratic Corpus) to the end of the second /beginning of the third century AD (date of the pharmaceutical treatises in the Galenic Corpus). I will write five chapters covering the strategies used by pharmacological compilers to establish their authority; the methods of source quotations in pharmacological writings; the involvement, real or imagined, of political figures in pharmacology; the appropriation of traditional remedies by medical writers; and parallel versions of recipes attributed to individuals. Building upon my previous research on pharmacological recipes, and drawing upon recent studies on the history of the book, this study will enhance our understanding of the construction and transmission of ancient medical knowledge.

Amount: £128,553
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development of a simple, rapid and affordable HIV RNA test for early diagnosisof HIV-infection in infants and for antiviral therapy monitoring in resource-limited settings. 27 Oct 2005

Recent initiatives such as that of the World Health Organisation to provide 3 million HIV-infected individuals with antiretroviral therapy (ART) by 20051 will increase the availability of HIV treatment in developing countries. Such large-scale treatment projects will also require diagnostics and a means to monitor treatment to be fully effective. In the developed world, measurement of HIV load is standard for diagnosis and monitoring of HIV-infected individuals. Currently available HIV load assays are unsuitable for resource-limited settings because they are complex, time-consuming and require expensive instruments and test kits as well as cold-chain shipment and storage of reagents. The availability of a simple and robust test for the determination of HIV load will be crucial for the successful implementation of HIV treatment in the developing world.The objective of this project is to develop a simple and rapid HIV RNA assay designed specifically to assist health care workers in developing countries both with the early diagnosis of HIV infection, particularly in neonates, and for HIV therapy monitoring when appropriate quantitation standards are included. The proposed assays will be based on visual detection of isothermally amplified HIV RNA by dipstick. Rather than reporting absolute quantification of viral RNA, the assay will give readout of clinically relevant thresholds.

Amount: £391,805
Funder: The Wellcome Trust
Recipient: University of Cambridge