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

Results

'PhD Workshop on History of Medieval and Early Modern Science and Medicine' to be held at the University of Cambridge on 23rd March 2007. 19 Feb 2007

PhD Workshop on History of Medieval and Early Modern Science and Medicine Although several excellent training programmes are available for PhD candidates, no specific support is available for students researching medieval and early modern science and medicine. These areas present particular challenges for students, often requiring the acquisition of language and palaeography skills, and the use of material which may be dispersed or incomplete. To address these problems, the workshop will open with a presentation on the issues which distinguish early history of science and medicine from other periods. This will be followed by a panel session on framing research questions from texts, objects, images, and quantitative data. After lunch, a second panel session will concentrate on acquiring or improving practical skills: languages (for instance, setting up support groups, such as Cambridge's Latin Therapy); palaeography; electronic resources; and approaching archives and collections. Each panel will be illustrated by texts and objects from the Whipple Museum's valuable collection of scientific and medical artefacts. The workshop will close with a Q&A session, in which participants will be encouraged to put questions to other students as well as to the panellists. Throughout, particular emphasis will be placed on student interaction and feedback. Feedback forms will be issued early on, with students encouraged to add to these throughout the day. They will also be asked to submit in advance an abstract of their research interests, which will be compiled in a booklet together with their contact details and a list of relevant PhD resources.

Amount: £602
Funder: The Wellcome Trust
Recipient: University of Cambridge

Schistosomiasis, hookworm and atopy in Uganda: IgE function, regulation and immunity. 05 Oct 2007

Key goals: Two schistosomiasis/hookworm treatment-reinfection studies in cohorts exposed to both infections, with detailed GIS and exposure analysis to give precise immunity estimates, and associations between infections controlled for overlapping transmission clustering. Study 1: compare first and second treatments for post-treatment immunological changes, and responses to in vivo Ag released from killed worms, for evidence of specific and non-specific cross regulation, affecting reinfection immunity. Specifically, measure: Schistosome, hookworm and aeroallergen IgE responses; Specific IgE function in passive histamine-release with Ag stimulation; Number/phenotype of circulating basophils and eosinophils, and tissue mast cell activity. Study 2: repeat most informative Study 1 assays, in relation to cellular responses: Whole-blood cytokine responses to schistosome and hookworm Ags; Active histamine-release from whole-blood samples stimulated native & recombinant schistosome, hookworm, aeroallergens; IL-10 and TGF-beta effects on in vitro cytokines induced by schistosome and hookworm; Skin-prick reactivity to aeroallergens; Identify cellular sources of IgE/IgE-effector modulatory molecules. Test hypothesis that: (a).Eosinophils have a regulatory role; in turn affected by immune modulators; non-responsive eosinophils are associated with reinfection susceptibility, (b).Susceptibility to schistosomiasis and hookworm is linked, via mechanisms that also affect allergy. (c).Life-stage expression and molecular structure of schistosome allergen-like Ags influence IgE and IgE-effector function triggering.

Amount: £2,027,513
Funder: The Wellcome Trust
Recipient: University of Cambridge

Measuring and modelling the dynamics of retinotopic map formation. 10 Oct 2007

It is not known how axons are guided to make appropriate connections at their target. We examine the paradigm case of the ordered map of connections between vertebrate retina onto contralateral superior colliculus (or optic tectum). We aim to understand how signalling cues arising from neuronal activity and from specific molecules interact to form this map. We will integrate our expertise in computational modelling with electrophysiological mapping and quantitative molecular techniques. The a nimal of choice is the mouse, in which it is possible to measure connectivity patterns resulting from disturbance, by genetic means, of activity-based and/or molecular-based signalling. Using contemporary imaging techniques, we will visualise the connectivity patterns formed at a resolution that is sufficiently high to enable us to develop a biologically-realistic quantitative computational model that will guide our experiments. To achieve our goals, we will trace the development of the mapp ing in wild-type mouse and in selected mutants; these results together with data from the literature will be used to constrain our model of this dynamic process, which will incorporate both activity-based and molecular signalling mechanisms; the model will be tested on our data from a more complex set of mutants.

Amount: £250,078
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Hagiography of Healing: Miracle Narratives as Discourses on Disease and Disability. 27 Nov 2007

This research sets out to explore how the medieval experience of disease and disability was mediated through the representations of healing miracles found in saints narratives. This goal will be achieved by exploring four main areas. The first will search these texts for evidence of practical healthcare; the ailments suffered and the treatments administered by the medieval medicus . The second part will situate these practices within the contemporary context by drawing upon sources such as Old English medicinal manuals, penitentials and sermons, with the aim of discovering whether the miracle narratives show a similarly syncretic attitude towards healing. The third part of this research will concentrate on the texts themselves, examining the manuscripts in which they were found, the scriptoria where they were produced and the conditions accounting for their composition. This will feed into a discussion of the narrative strategies employed by the authors and their subversion of the te xts testimonial format. The final section will consider the occasion of their communication; how these carefully crafted stories were relayed to the public. This will involve reconstructing the conditions of performance; assessing how the architectural and liturgical arrangements of the shrine may have affected the dissemination of the stories.

Amount: £104,895
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

Calcium-sensitive adenylyl cyclases and cAMP compartmentation. 16 May 2007

We wish to continue the study of Ca2+-sensitive ACs, along with the cAMP compartmentalization that is an inherent component in their regulation. Since we are beginning to suspect that ACs are no longer just centrally important generators of a critical second messenger but are also dynamic scaffolding platforms around which regulatory assemblies may be gathered, we need to know their partners in functioning signalling complexes. To understand the functions, interactions and regulation in the cell of Ca2+-sensitive ACs we want to extend what we know of the molecular requirements of Ca2+-stimulation and inhibition, by a combination of structure-function, structural and kinetic analyses; we want to know which proteins the ACs associate with, to identify the cellular features that confer Ca2+-sensitivity on ACs and to identify other components of AC microdomains; finally we wish to study cAMP dynamics in these microdomains in real-time in live cells, using rapid cAMP sensors and in situ str ategies, such as RNAi, to unambiguously assess the contribution of individual components in controlling cAMP. We feel that these three interdigitated experimental approaches provide the necessary powerful strategy to bring a true grasp of the complexity, flexibility and power that is cAMP signalling.

Amount: £1,019,885
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of cell adhesion dynamics during epithelial cell movements. 10 Jul 2007

Half way through embryonic development, the epidermis of Drosophila exhibits a gap covered by a different epithelium, the amnioserosa. Dorsal closure is the process whereby interactions between the two epithelia establish epidermal continuity. This process is an excellent model system to study the cellular processes involved in epithelial morphogenesis. While much attention has been focused on the cytoskeleton and its regulation during dorsal closure, little is known about the regulation of the cell-cell adhesion systems which must play a key role in the process ensuring the continuity of the epithelia and mediating their interactions. Here we propose to perform a quantitative cell biological analysis of the regulation and coordination of the components of the adherens junctions during dorsal closure. Using state of the art microscopic techniques we shall probe into the spatial and temporal dynamics of the interactions between DE-Cadherin and D- -catenin, Armadillo, as well as betw een a-catenin and Armadillo, and how these impinge on the coordinated movement of the epidermal sheet. In parallel we shall analyze how these molecular events that take place at the cellular length scale contribute to the behaviour of specific tissues and to the overall morphogenetic movement.

Amount: £281,392
Funder: The Wellcome Trust
Recipient: University of Cambridge

Screening and characterisation of novel platelet candidate genes derived from genome-wide association studies for function in relation to haemostasis and thrombosis in the model organism Danio rerio. 16 May 2007

Platelets play a central role in atherothrombosis (AT) and death from myocardial infarction (MI). Our research aims to determine to which extent platelet-gene sequence variation contributes to the risk of AT. Parallel strategies of genome-wide association studies in MI patients and in-depth studies of platelets with an aberrant functional phenotype by transcriptome- and proteome-based analysis, have identified candidate genes in platelets conferring risk for AT. This application addresses the ne ed for a high-throughput method of studying the function of those genes with a hitherto unknown role in platelets. Based on successful feasibility studies the zebrafish has been chosen, which has the unique advantages of being both genetically tractable and a relevant model organism for studying vertebrate haemostasis. Protein translation from ~100 genes will be blocked using antisense oligonucleotides, and phenotypes of spontaneous bleeding or altered kinetics of laser-induced thrombus format ion recorded. Detection of subtle gain- and loss-of-function phenotypes will be enhanced using genetically-modified zebrafish predisposed towards bleeding or thrombosis. The most promising genes will be characterised in even greater detail using null mutants created by target-selected mutagenesis (TILLING). Together with functional studies on humans, these studies will contribute to an increase in knowledge of the mechanism of AT.

Amount: £223,296
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structure function relationships of rotavirus RNAs - significance for the replication cycle. 24 Apr 2007

Rotaviruses are a major cause of acute gastroenteritis in infants and young children worldwide, leading to approximately half a million deaths per annum. There is no recognised specific antiviral treatment, and whilst rotavirus vaccines are under development they have not been universally applied yet. Rotaviruses package 11 different RNA segments into each virus particle. Reassortment between viruses occurs by exchange of corresponding RNA segments. Much published work indicates that this precis ion of packaging is a consequence of specific RNA structures in the RNA segments and that the RNA fulfils a structural role in the virion. We have performed preliminary analysis of potential RNA secondary structures in the termini of rotavirus segments and have identified conserved sequences and conserved potential intra and intermolecular pairings between the segments. Our aim is to define the RNA packaging signals in rotaviruses by structural analysis using free energy parameters, biochemical probing, sequence comparison and NMR spectroscopy. We will validate solved structures functionally by interaction with rotavirus core proteins and in replication assays and attempt to develop an in vitro packaging system. This work will identify new candidate therapeutic targets and has potential in vaccine development. It will contribute towards a reverse genetics system for rotaviruses.

Amount: £397,294
Funder: The Wellcome Trust
Recipient: University of Cambridge

'Secrets and Knowledge: Medicine, Science and Commerce, 1500-1800' symposium to be held at Cambridge University on 15-16 February 2008. 17 Oct 2007

Secrets played a central role in transformations in medical and scientific knowledge in early modern Europe. As a new fascination with novelty began to take hold from the lat fifteenth century, Europeans thirsted for previously unknown details about the natural world: new plants, animals, and other objects from nature, new recipies for medical and alchemical procedures, new knowledge about the human body, and new facts about the way nature worked. These 'secrets' became popular items of commerce and trade, as the quest for new and exclusive bits of natural knowledge met the vibrant early modern marketplace. Whether disclosed widely in print or kept more circumspect in manuscripts, secrets helped drive an expanding interest in nature throughout early modern Europe. The conference will provide a much-needed forum to explore recent research on the circulation of secrets in medieval and early modern medicine and science. As the first conference in over two decades to focus exclusively on this crucial genre, it will assess the advances and transformations in our understanding of secrets' role in the development of natural knowledge across early modern Europe.

Amount: £3,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Low affinity Fc receptors, immune regulation and disease. 24 Oct 2007

We will continue our long-standing efforts to understand the biology of low affinity Fc receptors, in particular FcgammaRIIb and FcgammaRIIIb, and their effect on disease. In particular we will follow up our recent observation that FcgammaRIIb is critical for plasma cell survival, to define its role in maintaining B cell tolerance, and thus how it contributes to autoimmune disease. We will use recently generated as well as new mouse models to define the involvement of FcgammaRIIb in autoimmune disease as well as in infection, with these mouse studies being carried on in parallel to functional and genetic studies in humans. We will also investigate FcgammaRIIIb, an activatory low affinity Fc receptor, defining the functional impact of copy number variation, and correlating this with susceptibility to autoimmunity (in particular vasculitis) and both pneumococcal and malarial infection. Finally we will take novel approaches to targeting each of these two receptors in the hope of using the knowledge we have gained about them to open new therapeutic pathways in autoimmunity and infection.

Amount: £1,724,836
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structural and functional neuroimaging studies in adolescents with disruptive behaviour disorders. 10 Oct 2007

In this project, we will use event-related functional magnetic resonance imaging (fMRI) to investigate whether adolescents with early-onset CD exhibit a differential pattern of neural activation during the fear conditioning process relative to adolescents with adolescence-onset CD and healthy controls. We will also measure brain activation while participants are viewing emotional pictures from the International Affective Pictures System (IAPS) to replicate and extend findings from the only prev ious functional imaging study in children with CD. The final functional task will be a probabilistic reversal task, which will enable us to examine differences in the neural substrates of reward processing and decision-making. In addition to functional studies, we will assess prefrontal cortex, anterior cingulate cortex, and amygdala volumes and morphology in this sample using automated structural MRI methods (voxel-based morphometry). Functional connectivity between these regions will be meas ured using network modelling approaches. This will be achieved using a cross-sectional case-control design involving an existing sample (n=73) of 14-18 year old post-pubertal adolescents with CD, consisting of cases with early (n=43) and adolescence (n=30) onsets ascertained from a community population. These groups will be compared with age- and sex-matched controls (n=40) with no lifetime history of antisocial behaviour.

Amount: £221,061
Funder: The Wellcome Trust
Recipient: University of Cambridge

Value in People Award. 17 Oct 2007

Not available

Amount: £350,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development and Expansion of the FlyMine/InterMine Project. No-cost extension of 8 months beyond original extension. Original end date 31/03/09. SA. 10 Jul 2007

The original FlyMine grant had several interlinked goals. Primarily we set out to integrate diverse Drosophila datasets to facilitate basic biological research on this tractable model organism. To support the genomic analysis of the important disease vector Anopheles gambiae, we also integrated genome data from the mosquito with the richer Drosophila data. We set out to develop a flexible query interface to the integrated data, allowing more complex data mining than simple record retrieval. We engineered the overall system to be generic, freely available and suitable for application in other areas for building both small and large-scale databases. We now seek to maintain and build upon these achievements by increasing the scope of FlyMine in terms of breadth of organisms and depth of data types covered. We propose further developing the underlying InterMine infrastructure to increase functionality, further improving the range of embedded tools within FlyMine and providing easy r outes for interaction with external tools. Finally, we will continue to facilitate the application of InterMine to other projects by external groups and provide training for users and developers.

Amount: £397,102
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genes and Mechanisms in Type 1 Diabetes. 07 Jun 2007

Type 1 diabetes (T1D) has a strong genetic basis, and results from autoimmune destruction of the pancreas. Several genes are known to be important, but many others have not yet been identified. Preliminary results from a genome scan by the Wellcome Trust Case Control Consortium have revealed a region on chromosome 16p13 associated with T1D susceptibility. This area contains 3 potential candidate genes: KIAA0350, MHC2TA and SOCS1, which are all known to influence immune responses. MHC2TA has pre viously been ruled out as a casual variant, however the role of the other two genes in T1D has not been established. The key goals of the proposed project are to investigate SOCS1 and KIAA0350 genes to establish: 1. Whether gene polymorphism is associated with risk of T1D 2. Whether phenotypic differences are present in individuals with susceptible and non-susceptible genotypes, potentially implying a mechanism by which pancreatic destruction might be promoted. As well as improving out improve our ability to predict which individuals are at a genetically higher risk of T1D, evaluation of the function of genes leading to an increased risk of T1D, will provide insights into gene function and pathogenesis of disease, allowing novel therapeutic strategies to be developed.

Amount: £294,835
Funder: The Wellcome Trust
Recipient: University of Cambridge

Delineation of discrete brain circuitry regulating obesity and type 2 diabetes in mice. 28 Mar 2007

Recently, substantial support for central serotonin (through 5-HT2C and 5-HT1B receptors) and melanocortin (through melanocortin4 receptors (MC4Rs)) systems in the regulation of energy balance and insulin/glucose homeostasis has been reported in genetic and pharmacological studies. Linking these two key pathways together, my laboratory recently observed that 5-HT2C/1B receptor agonists promote hypophagia and produce improvements in insulin and glucose regulation in a MC4R-dependent manner. Here I propose to identify discrete populations of upstream serotonin- and downstream MC4R-expressing neurons underlying the serotonergic modulation of energy balance and glucose homeostasis and to determine the importance of activity at the endogenous melanocortin agonist (POMC/ -MSH)/antagonist (AgRP) and serotonin 5-HT2C/5-HT1B receptors in these effects. Finally, I will identify peripheral target tissues through which serotonin-MC4R pathways affect satiety and glucose metabolism. Aim 1 : To identify discrete populations of serotonin neurons involved in the modulation of energy balance and glucose homeostasis. Aim 2: To determine whether regulation of POMC/AgRP and activation of 5-HT2CR/5-HT1BR underlies serotonin s effects on energy balance and glucose homeostasis. Aim 3: To identify and characterize distinct populations of MC4R-expressing neurons critical for serotonin s effects on energy balance and glucose homeostasis. Aim 4: To identify key downstream periphera l mechanisms of central serotonin-MC4R-regulated satiety and glucose metabolism.

Amount: £1,049,233
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanism of parasite mediated suppression of autoimmunity. 12 Dec 2007

The development of autoimmune diseases such as Type 1 diabetes is influenced by both genetic and environmental factors. Data from both animal models of human autoimmune diseases and from human inflammatory and autoimmune conditions suggest that infections and in some cases products of infectious agents have the capacity to prevent or ameliorate autoimmune pathology. In this application the products of two different infectious agents (Bordetella pertussis and Fasciola hepatica) that have been sho wn to have immunoregulatory properties will be used to prevent onset of Type 1 diabetes in the NOD mouse. The ability of these products to modulate dendritic cell function in vitro and their potential to influence T cell differentiation will be assessed. NOD mice also develop a relapsing EAE following immunisation with antigens such as MOG. This makes them a good model of human MS. The ability of infection with Fasciola hepatica or of its excretory secretory product (ES) to inhibit onset and rel apse in EAE will additionally be investigated.

Amount: £167,621
Funder: The Wellcome Trust
Recipient: University of Cambridge