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Award Year:
2006
Currency:
GBP
Recipients:
University of Cambridge

Results

Needs, rights, and preferences in pharmaceutical ethics. 02 Nov 2006

The proposed research aims to provide a conceptual analysis of the claims of needs versus those of rights and preferences as a way of tackling the pharmaceuticals ethical complexity. In doing so, it will relate the question of what makes drugs different from other valuable commodities to a broader one, i.e.: What makes healthcare a sui generis social good? Subsequently, the project will engage with issues in healthcare ethics, global ethics and political philosophy, e.g. equitable access to hea lthcare at national and global levels. An additional goal of the research is to broaden the theoretical framework for assessing regulation and policy alternatives concerning pharmaceuticals and to inform the public debate about these. The research will apply the methods of analytic philosophy in the following three stages: 1) background research; 2) statement of preliminary findings and initial feedback; 3) writing up and communication of the final results. These will be disseminated in formats, tailored to the target audiences (academics, regulators, and interested parties): 1) articles in peer-reviewed journals; 2) a monograph; 3) conference papers and a concise report downloadable from the website of Cambridge University, Faculty of Philosophy.

Amount: £125,263
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of immunosenescence in chronic hepatitis C infection. 07 Dec 2006

Introduction: Hepatitis C virus (HCV) affects 0.2 - 1% of the UK population causing cirrhosis, and hepatoma in a variable proportion. Factors that increase risk of progressive liver injury include male sex, immune suppression, alcohol abuse and critically, increased age. Many studies indicate an association between broad defects of T-cell responses (specific and non-specific) and persistent infection, which may be reversed by antiviraltherapy. Reduced immune function with ageing (immunosenescence) may be accelerated by chronic viral infection. Aim: To determine whether accelerated immunosenescence is present in patients with chronic HCV infectionand correlates with impaired immune responses to HCV or clinical outcome.Methods: Analysis of circulating/intrahepatic lymphocyte phenotype and function using healthy controls matched for age, sex and CMV (i) cross-sectional study of HCV exposed subjects of varied age and severity of liver disease with and without viraemia (ii) longitudinal study of HCV infected patients undergoing antiviral therapy or transplantation for cirrhosis or hepatoma. Finally to investigate circulating/intrahepatic lymphocyte phenotype in relation to HCV-specific T-cell function. Cell-surface phenotype for senescence associated markers, telomere length, cytokine production and proliferation will be analysed by flow-cytometry and correlated with markers of HCV outcome, including hepatic fibrosis, viral loadand response to antiviral therapy.

Amount: £134,019
Funder: The Wellcome Trust
Recipient: University of Cambridge

Screening a human genome-wide siRNA library. 27 Jun 2006

The human genome contains ~22,000 genes, over half of which code for proteins of unknown function. The Cambridge Institute for Medical Research and the Hutchison/MRC Research Centre have recently joined the Genome-wide RNAi Global Initiative to screen the entire human genome using the first-ever genome-wide siRNA library. We will use the library to deplete each gene product in human tissue culture cells, then carry out plate-based assays, high throughput flow cytometry, and automated microscopy to examine the phenotype. We will assay for effects on endocytosis, secretion, organelle dynamics, autophagy, viral down regulation of immunoreceptors, cell motility, and mitosis. To carry out these experiments, we will need robotics, readout equipment, and a full-time "Librarian" who will oversee the distribution and screening of the library. We anticipate that many of the genes we identify as important in a particular pathway will turn out to participate in other pathways as well, so our screens should be complementary. By grouping together previously uncharacterised genes based on knockdown phenotype, we should begin to get a handle on protein interaction networks. Ultimately, we hope to find hundreds of new players, both in fundamental cellular pathways and in various disease states, and to learn how they function.

Amount: £844,583
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Molecular mechanisms in human insulin resistance. 23 Feb 2006

Our programme of research in human severe insulin resistance has been continuously supported by the Wellcome Trust since 1991. It has led to the discovery of several, novel molecular explanations for insulin resistance, linked those molecular defects to in vivo pathophysiology, translated research into clinical diagnostics and catalysed developments in research infrastructure and the independent careers of young investigators. Our specific aims over the next five years are i) To enhance the quality and size of our cohort of subjects with severe insulin resistance ii) To better understand the pathophysiology of disorders we have discovered, in particular the syndrome of AKT2 deficiency iii) To define novel molecular mechanisms of severe human insulin resistance. This will involve the functional genomic study of mutations we have recently found in five candidate genes, PRKAB1, GPLD1, PRKCQLIPE, FOXO3A and studying the properties of other novel variants that will emerge. In addition, we will look for sub-microscopic chromosomal abnormalities in subjects with insulin resistance and complex developmental features by comparative genomic hybridisation iv) To enhance our translational studies in human in vivo physiology and, ultimately, therapeutic trials v) To utilise our discoveries in severe insulin resistance to inform genetic studies in common metabolic disorders.

Amount: £1,380,038
Funder: The Wellcome Trust
Recipient: University of Cambridge

Specification of Circumferential Ascending Interneurons in Zebrafish Spinal Cord. 04 Jul 2006

Our ability to treat neurological disorders or spinal cord injuries is currently constrained by our limited understanding of how the central nervous system develops and functions. In particular, we know very little about how different functional types of interneurons develop. The key goal of this research is to understand how a specific functional class of vertebrate interneurons, Circumferential Ascending interneurons (CiAs), are specified in zebrafish spinal cord. We will test the spec ific hypothesis that Hedgehog, Retinoic Acid and BMP signalling pathways interact to specify the CiA domain in vivo. We will also determine the individual and combined functions of Pax2 and Engrailed1 in the specification of different CiA characteristics, including neurotransmitter expression; cell morphology; axon trajectory; synapse formation and correct activity during embryonic swimming behaviour. In many of these experiments, we will use stable transgenic-GFP lines to observe CiA deve lopment in live embryos. As CiAs share many characteristics and are probably functionally homologous with amniote V1 cells our findings should also be applicable to mammals. This research will significantly increase our understanding of vertebrate interneuron development and it will also facilitate future studies to establish causal links between particular genes and CiA activity during specific behaviours in live embryos.

Amount: £246,134
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular genetics of planar polarity in Drosophila 21 Feb 2006

Planar cell polarity (PCP) is exemplified by the direction of ciliary beat, the orientation of hairs or the alignment of stereocilia. The problem is pervasive and long range (how does information set up over an entire developing field convey axial information to single cells?) and local (how does a single cell read this polarising information and how does it liaise with its neighbours?). We have worked on PCP for 9 years using the Drosophila abdomen. We and others have shown that PCP depends on a novel mechanism. The pervasive system relies on interacting cadherin molecules (Dachsous, Fat) and the local system depends on the Frizzled receptor and another cadherin, Flamingo. We have published evidence that each cell is polarised by comparing the levels of activity of Frizzled in its neighbours, using the intercellular bridge made by Flamingo to do so. Now we want to test this model at the molecular level, using constructs made with all three cadherins and with Fz, assaying them both in flies and in cell culture. We will also investigate the long range system, asking how it receives information from the organising morphogen (Hedgehog) upstream and passes information to the local system downstream

Amount: £389,685
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Z alpha-1 antitrypsin in the pathogenesis of emphysema. 23 Feb 2006

Alpha-1 antitrypsin (AT) is a major serine proteinase inhibitor whose main function is to protect the lung from proteolysis by neutrophil elastase. The Z variant (E342K) is prone to form polymers which accumulate as inclusions in the hepatocyte predisposing Z-AT homozygotes to cirrhosis. The low plasma levels of Z-AT predispose early onset panacinar emphysema. Polymeric AT may in part be responsible for the previously described exaggerated inflammatory response in Z-AT homozygotes. Polymers of Z-AT are present emphysematous lungs, and are chemotactic to neutrophils and preliminary data suggests that they also induce the secretion of interleukin-8 from type II alveolar cells. The factors that cause the formation of polymers within the lung are not known. In vitro, their formation is accelerated by increasing concentration and temperature. Furthermore, Based on the structural biology of polymerisation we have identified peptide inhibitors of polymerisation. The key scientific objectiv es of this work are to (1). elucidate the factors that cause polymerisation of Z-AT within the lung (2). assess whether polymeric AT causes Interleukin-8 secretion from type II pneumocytes (3). to assess whether potential therapeutic agents are efficacious in vivo.

Amount: £126,420
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

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

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £300,000
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

The control of lymphatics in autoimmunity. 07 Dec 2006

The immune system has evolved to defend the host from invading pathogens. This powerful system must be tightly regulated by inhibitory mechanisms. Failure of such regulatory mechanisms can result in autoimmunity. Following an infection, lymphocytes and antigen presenting cells are trafficked from sites of inflammation by a network of lymphatic vessels into draining lymph nodes. The lymph node and lymphatic vasculature subsequently expand to facilitate the immune response. Recent evidence su ggests that B cells and macrophages play a critical role in this process through the production of lymphangiogenic factors such as VEGF-A and VEGF-C. Many autoimmune diseases are characterised by defective immune inhibition and B cell hyperactivity. I propose to determine how deficiency of inhibitory receptors affects lymphangiogenesis and the development of autoimmunity, and whether inhibition of lymphangiogenesis might prevent or treat autoimmune disease. I intend to study the production of lymphangiogenic factors in vitro by B cells and macrophages isolated from mice with defective immune inhibition, and by human B cells and macrophages with dysfunctional inhibitory receptors or from patients with autoimmune disease. I will also investigate lymphangiogenesis in autoimmune-prone mice in vivo and develop novel mouse models and imaging techniques to characterize lymphangiogenesis and lymphatic-leukocyte interactions in autoimmunity.

Amount: £801,111
Funder: The Wellcome Trust
Recipient: University of Cambridge

Clinical, Cellular, and Molecular Characterisation of Novel Syndromes of Abnormal Growth and Insulin Action. 07 Dec 2006

Insulin resistance (IR) is a central feature of T2DM, and insulin sensitization both delays T2DM onset and mitigates the effects of established T2DM. Nevertheless, its mechanisms are incompletely elucidated. I have identified 2 novel syndromes of severely abnormal insulin action and growth, the first including extreme IR, dwarfism, and chromosomal instability, and the second constitutive insulin-like activity, somatic hemihypertrophy and tumorigenesis. My aim is to gain novel insights into ins ulin s role in controlling cellular metabolism, division, and senescence through correlation of clinical, cellular and molecular features of these 2 syndromes. Specifically: 1) Intermediary metabolism will be comprehensively characterized in vivo. 2) Primary lines of fibroblasts and EBV-transformed lymphoblastoid cells (EBVLs) will be established and systematic study of cell cycle checkpoint controls and DNA damage responses undertaken using a combination of approaches including pharmacological inhibition of key enzymes, siRNA-mediated gene knockdown and genetic complementation. 3) Insulin signalling in primary cells will be examined, using additionally microarray transcriptomics and unique IR control cells. 4) Candidate gene screening will be guided by these studies. 5) Identification of the causative gene will lead to specific manipulation of its function in vitro, and genetic association studies to determine its role in common type 2 diabetes.

Amount: £674,660
Funder: The Wellcome Trust
Recipient: University of Cambridge

A prospective investigation of gene expression profiling in primary systemic vasculitis 07 Dec 2006

The primary systemic vasculitides are a group of complex, heterogeneous and poorly understood autoimmune disorders. A lack of clear guidelines on whom to treat with what, when and for how long results in a high associated morbidity and mortality. We aim to sample PSV patients at presentation with active disease and during several different treatment protocols as part of ongoing clinical trials and make detailed comparisons with gene expression seen in healthy controls and in another important, related autoimmune disease, SLE. Previous studies have analysed RNA derived from whole PBMC. We aim to analyse RNA collected from separated cell subsets using oligonucleotide microarrays and to correlate expression signatures with extensive clinical data. We then aim to validate such expression profiles as markers of diagnosis, prognosis, response to treatment and treatment-related toxicity by expanding our initial cohort and with the design of further clinical trials. Preliminary data included here confirms the validity of this approach and hints at interesting correlations to be pursued.

Amount: £242,463
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infection and Immunity. 26 Apr 2006

Not available

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

CD40 and CD154: breaking and maintaining peripheral tolerance to pancreatic beta cells. 08 Feb 2006

CD40 and CD154: Breaking and maintaining peripheral tolerance to pancreatic beta cells 1. To determine the regulatory capacity of CD40-induced CD4+CD25+ T cells and the role of CD40 in their expansion. 2. To determine the point of divergence between the CD40 and TNFa signalling pathways and how this leads to distinct cellular outcomes. 3. To determine the role of TNFa in the prevention of CD40-induced expansion of CD4+CD25+ T cells.

Amount: £7,584
Funder: The Wellcome Trust
Recipient: University of Cambridge

The structural biology of cell signalling and regulation: multiprotein systems and the achievement of high signal-to-noise ratios. 27 Apr 2006

The control of cell differentiation, growth and proliferation is mediated by the assembly and disassembly of multiprotein complexes. My group has studied the 3-D structures of many such complexes in order to understand the nature ofthe interactions, organisation and cooperativity; examples are FGFR, human recombinase Rad51, the breast cancer associated gene product BRCA2, and Cdk6 with cell cycle inhibitor p19INK4d. We have shown that pair-wise interactions are often weak and ill-defined but lead to cooperative assembly of multiprotein complexes with well defined structures, so providing better signal-to-noise ratios in signalling. In this proposal I focus on other features that are shared between multiprotein systems at the cell surface, in the cytoplasm and in the nucleus. I plan to investigate 3-D structural features of complexes where: 1. One or more components are disordered prior tobinding. 2. Higher order clustering modulates signal transduction.3. Glycosylation controls receptor interactions. 4. Different assemblies regulatedifferent signalling pathways. In order to achieve these objectives I plan notonly to extend studies on systems where we have worked before, for example FGFR, Met receptor and Xrcc4; but also to initiate work on others where we have only preliminary studies, such as the Notch receptor. The research involves protein expression, purification, characterisation of complexes, crystallisation, X-ray analysis and bioinformatics.

Amount: £1,454,930
Funder: The Wellcome Trust
Recipient: University of Cambridge