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Currency:
GBP
Recipients:
University of Cambridge
Award Year:
2007

Results

Development of the Xenopus and Zebrafish Retina. 10 Oct 2007

The proposed research on mechanisms of neural development, uses the Xenopus and zebrafish retina as model systems. The key goals of this programme of work are: 1. To investigate the embryonic origins of the retina and in particular to elucidate the signalling pathways involved in the multistage induction of the eyefield from uncommitted and multipotent ectodermal tissue. 2. To characterize the role of the Zic transcription factors in optic cup proliferation and patterning, and to underst and the interaction of Zic proteins as putative integrators of Hedgehog and Wnt signalling in this process. 3. To probe the mechanisms of interkinetic nuclear migration that characterizes proliferating neuroepithelial cells in the retina. 4. To uncover the mechanism by which Hedgehog and Wnt signaling participate in the transition from slow dividing undetermined retinal stem cells to rapidly dividing neural precursors. 5. To extend our knowledge of how specific neurons arise in the reti na by tracing distinct lineages in real time with dynamic imaging in normal and mutant environments. This work continues our longstanding commitment to take advantage of the remarkable opportunities that the vertebrate retina in these model systems provides to open up new issues in the general field of neural development.

Amount: £1,579,946
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cross-talk between Notch and TNF signalling pathways: role of dTraf1. 31 Oct 2007

SUMMARY Signalling between cells and tissues is critical for their development and for their continued modulation post-embryonically. Several key signalling pathways, which include the Notch pathway, have been implicated in mediating this communication during development. In contrast, other pathways, notably the pro-inflammatory Tumour necrosis factor (TNF), have predominantly been considered in the context of the immune response and tissue homeostasis. From our investigations into targets of N otch activation we have found that dTraf1, a key signalling adaptor for the TNF receptor is up-regulated following Notch activation, suggesting a potential link between Notch and TNF pathways. This raises questions about the contribution of dTraf1 and the TNF pathway to developmental patterning and conversely about the contribution of Notch to modulation of the immune response. Here we propose to investigate these questions, using Drosophila melanogaster as a model. AIMS The aims of our prop osed research are 1. To determine the extent of cross-talk between Notch and dTraf1 and its consequences; 2 To ascertain the roles of dTraf1 in developmental signalling and its relationship to TNF/TNR signalling; 3. To identify domains in dTraf1 required for its function and localisation in different signalling contexts.

Amount: £173,569
Funder: The Wellcome Trust
Recipient: University of Cambridge

Formation and Function of Insulin-producing Neurons in Drosophila. 12 Dec 2007

Insulin and IGFs are key coordinators of growth and metabolism in multicellular organisms. I have identified a set of neurons that express Ilp7, one of the Drosophila insulin-like peptides. These neurons are distinct from the known insulin-producing cells of the Drosophila brain that secrete into the circulation and regulate global growth. Instead, Ilp7 neurons contact the hindgut muscles, thus raising the possibility that they regulate local gut functions. This proposal is aimed at: 1) characte rizing the developmental and physiological functions of Ilp7 neurons 2) identifying new factors regulating the survival and differentiation of Ilp7 neurons. To investigate the functions of Ilp7 neurons, I will use RNA interference to downregulate Ilp7 expression and the Gal4-UAS system to silence/ablate these neurons. Gut development and physiology will be assessed using defined local and whole-organismal parameters. To identify new genes specifying Ilp7 identity, I will carry out a high-through put F1 screen of pre-mapped mutant lines. The readout for this screen utilises a double reporter line, allowing Ilp7 neurons to be visualised in living embryos under the microscope. Finally, in a candidate gene approach, I will investigate the mechanisms by which homologues of known vertebrate insulin and enteric regulators control insulin production in Ilp7 neurons.

Amount: £637,016
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cys-loop receptors: relating structure to function. 28 Mar 2007

The aim of this project is to define the structural basis of the mechanism of action of the Cys loop family of neurotransmitter receptors. The roles and specific chemical interactions of amino acid residues in both 5-HT3 and GABAc receptor binding sites, and in the protein subdomains that link and drive channel opening, will be characterised, using both theoretical (modelling, docking, molecular dynamics) and experimental approaches (mutagenesis, radioligand binding, functional assays, fluoresce nce measurements, structure determination). The key goals are defining (a) the molecular interactions that are critical for the binding of 5-HT or GABA and other agonists and antagonists; (b) the molecular interactions in the binding site that initiate receptor gating; (c) the conformational changes that occur in the extracellular ligand-binding site as a result of agonist binding; (d) how these changes are transduced to the pore lining M2 domain; and (e) how M2 moves to open the channel.

Amount: £1,669,391
Funder: The Wellcome Trust
Recipient: University of Cambridge

Towards a quantitative understanding of in vivo protein aggregation. 30 May 2007

Assemblies of misfolded proteins are associated with a range of neurological and systemic human disorders whose detailed molecular mechanisms are not understood in any detail. Key for generating a better understanding of protein interactions and dynamics is the synergy between experiment and theory, which creates a link between protein chemistry and human diseases. This proposal describes the use of computational methods in combination with biophysical experiments and studies of Drosophila model s and aims to reveal the molecular processes involved in protein assembly. By using alpha-synuclein as a model system, a protein of great medical relevance that is highly tractable both experimentally and computationally, I aim to develop a quantitative understanding of in vivo aggregation. To achieve this, I will generate rationally an extensive set of alpha-synuclein variants and analyse their in vitro aggregation mechanism in the presence of different biological factors. These results, combin ed with the measured effect of these variants on neurodegeneration in transgenic Drosophila, will be used to develop a mathematical description of in vivo protein aggregation. As well as providing unprecedented knowledge of the mechanism of protein association, the goal is also to develop widely applicable methods of screening amyloidogenicity of entire proteomes and of preventing assembly.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biology Zone: Cambridge Science Festival, Schools' Visits and Online 30 Jan 2007

We intend to run novel participative Biology Zone activities at the Cambridge Science Festival during National Science Week in March 2007, through school visits and online through interactive content, audio and video material. The Biology Zone will engage school pupils, young people and adults with interactive presentations, demonstrations, and take-home activities on the health, social and ethical dimension of advances in genetic research, stem cell research, the effects of pharmaceutical drugs on the body, nutrition and farming, cancer research, psychology and neuroscience and infectious disease. In collaboration with partners with extensive track records in this area, the Biology Zone will involve scientists presenting interactive experiments, displays and computer presentations, and discussing issues with 3,000 visitors of all ages. Schools visits are planned to reach a further 1300 pupils, focusing on schools in challenging circumstances, with a combination of scientists and artists visiting schools and school groups visiting farms and other sites of interest to support learning in biological subjects. Online activities will bring interactive biomedical brainteasers and puzzles, targeted at 11-18 year olds, on to the Cambridge Science Festival site to give learning an extended dimension. We will also make Podcasts and audio downloads of biomedical content at the Cambridge Science Festival available through our website, in partnership with the Naked Scientists' radio show. Videos of biomedical lectures and of Festival attendees presenting their views will also be made available through our website. These online activities will engage at least 10,000 visitors.

Amount: £25,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

The CD40-CD154 pathway in FoxP3+ regulatory T cell biology. 23 Mar 2007

This project aims to investigate the role of CD40-CD154 signals in the development of Foxp3' regulatory T cells. Specific aims include: 1) Elucidating the genetic events which are manipulated by this signal in pre-committed and committed Foxp3'Tregs 2) Ascertaining whether direct signalling through CD154 molecule is essential for Foxp3'Treg development 3) Determining the genetic and molecular events that lead to dependency on the CD154-CD40 pathway for Foxp3'Treg development in an ageing immune system

Amount: £144,363
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of envelope proteins in the outcome of lentivirus infections in hominoids 23 Mar 2007

The overall aim of the project is to better characterise the non-pathogenic HIV-1 and SIVcpz infection of chimpanzees, where a high viral load is maintained without progression to AIDS, and to determine the factors that result in this non-progressive outcome. Determining the differences between pathogenic infection of humans and non-pathogenic infection of our closest relative will provide unique insight into the pathogenesis of HIV-1 infection, which remains poorly understood after over 25 years of research. Key differences described so far are that non-pathogenic infection of chimpanzees does not result in chronic immune activation or NK cell dysfunction shown in pathogenic infections of humans. In both of these phenomena, the majority of effected cells are not infected, suggesting a viral protein can induce these effects independently of cellular infection. Viral envelope on the viral surface, or in a soluble form following shedding, can interact with a number of receptors. Interactions with NK-cells and HIV-1 envelope leads to NK-cell dysfunction, and interaction with T -cells can induce virological synapses, a structure similar to the immune synapse involved in T-cell activation. This project will focus on immune dysfunction resulting from direct interactions between HIV-1/SIVcpz envelope and cells of the immune system purified from cryopreserved human and chimpanzee PBMCs.

Amount: £144,363
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetic analysis of tubule morphogenesis in Drosophila. 10 Jul 2007

An early consequence of the specification of renal cells in the hindgut of Drosophila is that tubule primordia branch out from this tissue. Later these short fat structures extend through the body cavity to form long thin tubules with a highly stereotypical 3-dimensional arrangement. Notably both the morphogenetic events and, in some cases, the genes that regulate, them are conserved between flies and vertebrates. We aim to understand how cell intrinsic factors combine with external cues to cont rol two of these morphogenetic movements; the initial branching events and the subsequent, directed elongation of tubules along defined routes through the body cavity. Specifically our goals are 1.to record details of the cells behaviour during each phase, using microscopy of fixed and living material. We shall focus on changes in cell shape, junctional dynamics and the position of cells relative to one another. 2. to show how differences in the gene expression of different tubule subtypes lead to the morphogenesis exhibited by each type. 3. to identify factors that promote tubule elongation and to understand their activities and interactions 4. to show how external cues promote specific responses in the outgrowing tubules and to relate these to the activity of intrinsic factors.

Amount: £445,918
Funder: The Wellcome Trust
Recipient: University of Cambridge

Expression and function coupling of P2Y1 and other P2Y nucleotide receptors in neurons. 06 Feb 2007

P2Y receptors are G protein-coupled receptor targets for extracellular nucleotides. Some of these receptors are or appear to be present in the brain but their function therein is not well understood. By expressing different P2Y receptors in sympathetic neurons, we previously showed that their activation can variously modulate several neuronal ion channels. Recently we have localized one such receptor (the P2Y1 receptor) to hippocampal pyramidal neurons and shown that activation of this receptor reproduces one of the effects observed in sympathetic neurons (inhibition of M-type K+ channels), thereby increasing neuron excitability. We also have found that P2Y receptors can co-localize with each other and with scaffolding synaptic proteins We now propose to: (a) produce a detailed immunocytochemical map of P2Y1 receptor distribution, first in the hippocampus and then in some other brain structures; b) complete functional studies of P2Y1 effects on hippocampal pyramidal neurons; c) investigate the homo-dimerization of P2Y1 receptors in sympathetic and hippocampal neurons, and possible hetero-dimerization with other P2Y receptors, by FRET and functional readout; d) clarify the molecular mechanism of P2Y mediated effect on M-channels; and e) investigate the involvement of scaffolding proteins in neuronal P2Y receptor function.

Amount: £230,244
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional characterisation of Kinesin using the Drosophila oocyte as a model system. 28 May 2007

The goal of this project is to understand how the motor protein Kinesin recognises its cargoes, achieves specificity in its transport and is regulated during Drosophila melanogaster oogenesis. Kinesin is a molecular motor that uses energy utilised from the hydrolysis of ATP to move cargo towards the plus ends of microtubules [1]. Kinesin-mediated cargo transport is conserved in vertebrate and invertebrates and is essential for cell viability. By using D. melanogaster oocytes as our model we have the opportunity to link the biochemistry, cell biology and genetics of Kinesin mediated transport directly to its essential function during development. The research topics of this project can be breakdown into three points: 1. Identification of Kinesin binding proteins and characterisation of their roles in Kinesindependent mechanisms. 2. Characterisation of the Kinesin domains required for its function during oogenesis. 3. Investigation into the functions of Kinesin phosphorylation.

Amount: £144,363
Funder: The Wellcome Trust
Recipient: University of Cambridge

Controlling notch protein interaactions in stem cell differentiation. 31 Aug 2007

The proposed project will focus on understanding and manipulating protein:protein interactions controlling stem cell differentiation with a particular focus on Notch receptors and ligands. Notch signalling occurs via direct cell:cell contact, links the fate of cells to their neighbours and plays a controlling role throughout development. Many aspects of the pleiotropic actions of Notch are recapitulated during neurogenesis from embryonic stem cells and this will form the biological focus of these studies. The project will build on existing work where we have demonstrate that blocking antibodies can be generated either by binding ligand (dll4) or by targeting EGF domains 11-14 of Notch 1. We will generate blocking and potentially activating antibodies to all members of the receptor/ligand family. This will provide specificity in blocking/activating Notch signalling which is currently unavailable using ligand based activation systems. The mechanism by which ligand binding permits release of the intracellular signalling domain is unknown. The project will test the hypothesis that activation of notch involves a ligand dependant release of a protective intra-molecular interaction, by screening directly for interactions between isolated groups of EGF domains. A number of Notch interacting proteins have recently been identified, including novel activators, inhibitors and molecules contributing to sub-cellular localisation. In addition we and others have generated evidence of ectopic distribution of Notch in some cells. We will specifically investigate the potential association of notch with supra-molecular signalling complexes, with a view to identifying alternative routes to manipulate notch signalling for research and potentially therapeutic applications.

Amount: £1,119,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interactions between polymorphic immuno-receptors and their consequences for disease susceptibility. 18 Jun 2007

Interactions between polymorphic immuno-receptors and their consequences for disease susceptibility. The MHC is a gene-dense region of fundamental importance to immune defence. About 40% of expressed MHC genes are involved in immune response to infection. The region is associated with most autoimmune conditions as well as infections and other diseases. Several genes in the complex particularly class I and II are polygenic and polymorphic. These characteristics reflect their co-evolution in response to infection but may also underlie susceptibility to chronic immunostimulation, particularly where polymorphic ligands and receptors are inherited independently. We have chosen therefore to investigate interactions between variable immunoreceptors, focusing on MHC-related and linked products and their partner molecules. In addition to class I and II, that are directly involved in antigen presentation, we will study the group of MHC-linked BTN/BTL molecules, related to CD80/86 coreceptors and other family members with the B30.2 domain. We will identify conditions for induction of their expression and their ligands on dendritic cells. Other MHC-related/linked genes, of major biomedical relevance, will include class I-like RAET, TAPBP-R and TREM. We will identify genetic and functional relationships between these genes, their encoded molecules and ligands. MHC interaction with NK receptors is a key example. We will study the consequences of inheritance of different combinations of polymorphic class I and KIR on disease in humans, complemented by data from transgenics, in collaboration with other groups.

Amount: £40,796
Funder: The Wellcome Trust
Recipient: University of Cambridge

Doctors, deaths, diagnoses and data: a comparative study of the medical certification of cause of death in nineteenth-century Scotland. 08 Mar 2007

The project will augment an already created dataset of some 38,000 death certificates from 4 communities in Scotland, 1861-1901, by adding the names of the doctors certifying the cause of death on each certificate. Three of the communities are rural, the remote Isle of Skye and the parishes of Rothiemay and Torthorwald, the fourth is the industrial town of Kilmarnock. Biographies of the certifying doctors will be constructed, as will individual and collective socio-economic profiles of their pat ients. This information will be used to assess the extent to which a doctor's age or date of qualification, the place and form of his medical training, his role within the medical provision particular to his community, or the characteristics of his patients influenced the causes of death which he recorded. A proportion of rural deaths went uncertified, and lay-reported causes of will be compared with medically certified. The findings will provide a deeper understanding of nineteenth century mortality patterns, as captured by published statistics generated by the civil registration system. They should also reveal the varying access to medical care available to patients depending on their social class, economic circumstances, or whether the community they lived in was urban, rural or remote .

Amount: £60,077
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structure, function and evolution of the trypanosome nuclear envelope . 05 Jul 2007

We seek a molecular characterisation of the trypanosome nuclear pore complex (NPC) and envelope. Our rational for initiating this project includes the divergent evolutionary position of trypanosomes, unique aspects of mRNA maturation (polycistronic transcription), unusual aspects of control of mRNA stability (primarily via elements within the 3 UTR) and a clear absence of a conventional (metazoan-related) nuclear lamina. We aim to: 1. Produce a high-resolution connectivity map of the trypano some NPC for definition of both composition and architecture. These data will facilitate a complete reconstruction of the trypanosome NPC for evolutionary and functional comparisons with yeast and mammalian NPCs. 2. Assess the functions of individual trypanosome nuclear pore proteins in terms of viability, structure and interactions with the nuclear lamina. Again comparison with studies in yeast and mammals will provide a framework for definition of divergence and conservation of function of sp ecific elements. 3. Initiate analysis of the trypanosome nuclear lamina. Currently this is unexplored, and our investigations have identified several strong candidates as components of this structure. All three aims will exploit a recently completed characterisation of the Trypanosoma brucei nuclear envelope proteome performed in collaboration between the applicants and the Chait laboratories (supporting data).

Amount: £285,279
Funder: The Wellcome Trust
Recipient: University of Cambridge

The nature of sensory comparison. 03 May 2007

Our experimental and theoretical work concerns the brain processes underlying the human ability to compare two spatially-separated objects with respect to a particular sensory attribute. The experiments are psychophysical and the subjects are healthy volunteers. In the present project, we shall concentrate particularly on two sensory attributes, the speed and direction of motion, but shall also perform key tests on other attributes, such as chromaticity, spatial frequency and orientation. We shall measure how the subjects' accuracy changes when the spatial separation of the discriminanda is increased, when a second attribute is varied, when multiple pairs of stimuli are presented, and when a noise field is interposed between the discriminanda. These manipulations are designed to distinguish between two classes of model, those in which discrimination depends on hard-wired detectors and those in which the comparison is between abstract, symbolic codes. We shall also undertake theo retical work, developing our concept of a 'cerebral bus', which would correspond to the major white-matter tracts of the brain. We would plan to complete a theoretical paper during the first year of the grant.

Amount: £57,260
Funder: The Wellcome Trust
Recipient: University of Cambridge

History of mammalian development in the UK: 1945-present. 17 Oct 2007

This small project is based on the analysis of 12 interviews with leading participants in two aspects of mammalian developmental biology in the post-war UK. One area of interest is in the research directions this field took, in particular given the increasing importance of molecular genetics from the mid-1960s onward. The second is in the resulting new applications to human reproductive technologies such as IVF and PGD, which led to significant social, ethical and political debate. As both a sig nificant episode of scientific research, and one in which scientists played an unusually prominent role in public debate, an interdisciplinary analysis of our interviews is appropriate. Our aim is to refine methods for future study, refine our research questions, identify relevant archives, and improve our practical skills. The longer-term aim of this project is to develop a larger bid for compilation of a public archive of materials related to post-war mammalian developmental biology in the UK .

Amount: £20,486
Funder: The Wellcome Trust
Recipient: University of Cambridge

The structural basis for the interaction of carbohydrates with PfEMP1 proteins in malaria pathogenicity. 24 Oct 2007

We have developed an expression system that allows us to produce large quantities of correctly folded, functional DBL domains from carbohydrate binding PfEMP1 proteins. We have also produced crystals of a chondroitin sulphate A (CSA) binding DBL domain. We will use these tools to investigate the structural basis for binding of CSA to this domain. (i) We will determine the structure of a CSA binding DBL domain. (ii) We will develop a quantitative binding assay to investigate the interaction be tween CSA and the DBL domain. (iii) We will use this assay to determine the minimum fragment of CSA that binds to the DBL domain. We will also mutate residues of the DBL domain that are predicted to play a role in CSA binding and determine the effect of these mutations on the interaction. (iv) We will grow crystals of the DBL domain in the presence of CSA disaccharides, and short defined fragments of CSA, enabling us to determine the structure of the complex between the DBL domain and CSA. ( v) We will express and purify heparan sulphate binding DBL domains and use similar structural and biochemical studies to investigate the interaction between the DBL domains and heparan sulphates.

Amount: £140,347
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular cell biology and pathology of hereditary spastic paraplegia. 07 Jun 2007

Our overall goal is to understand better the molecular processes involved in axonal maintenance and degeneration. We will do this by studying the hereditary spastic paraplegias (HSPs), genetic conditions in which long axons in the spinal cord degenerate. We will analyse the normal and pathological functions of two HSP proteins that we have identified as binding-partners, spastin and atlastin. These proteins are involved in processes at the interface between membrane traffic and microtubule re gulation. We will examine functional assays for selected membrane traffic pathways in cell models of spastin- and atlastin- HSP. We will explore a potential mechanism by which abnormal traffic in these pathways may cause axonal degeneration, by analysing whether defects in axonal transport of cargoes derived from them are an early feature in cellular models of spastin- and atlastin-HSP. In the light of our preliminary work suggesting its importance in one type of HSP, we will determine whether abnormalities in BMP signalling are a unifying pathological feature of a group of HSPs, including spastin- and atlastin- HSP. Finally, we will use yeast-two hybrid screening as a basis to identify unrecognised HSP protein interactions, to extend the HSP protein interaction network and to identify new HSP candidate genes.

Amount: £1,364,502
Funder: The Wellcome Trust
Recipient: University of Cambridge