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University of Cambridge

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The Total Archive: Dreams of Universal Knowledge from the Encyclopaedia to Big Data. 30 Jan 2015

The conference 'The Total Archive' and associated special issue of the journal LIMN deals with schemes for universal knowledge, from mass bio-sample collection and global demography to representations of totalities in film, fiction and visual art. The conference seeks to interrogate the practices of Big Data and the identity politics of sciences with grand explanatory claims, for example modern genomics. The conference takes place on March 19/20, 2015, at the Centre for Research in the Arts, Hum anities and Social Sciences (CRASSH), University of Cambridge. In addition to the urgent need to contextualise Big Data (see: http://www.mpiwg-berlin.mpg.de/en/research/projects/DeptII_Aronova_Oertzen_Sepkoski_Historicizing), the conference is timely because of the increasing use of large data-sets and aspirations to totality in the humanities themselves. For example CRASSH's own 'Visual Representations of the Third Plague Pandemic' is one such project represented at the conference. Theme s of mass data collection are also important outside the academy, and so the conference will feature a public lecture (by the literary theorist Katherine Hayles), and essays will be published in the popular open access journal LIMN (www.limn.it), which has agreed in principle to run a special issue on the topic.

Amount: £2,800
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diabetes and Inflammation Laboratory. 21 Apr 2015

Our goal is to identify clinical interventions in patients recently diagnosed with, or children at high risk of developing, type 1 diabetes (T1D), thereby maximising the health benefits of genetics and genomics in this common immune disorder. Our studies in T1D serve as a model for the investigation of other diseases and their treatment. We will take specific steps towards achieving this goal during the next five year programme: (1) Genetics. Define the genetic basis of T1D by fine-mapping di sease-associated causal variants and haplotypes, identify their target genes, and investigate the regulation of these genes before and after cell activation/differentiation. (2) Phenotypes and mechanisms. Identify aberrant cellular interactions and pathways caused by susceptibility genes that mediate a loss of immune tolerance to insulin-producing beta cells culminating in their destruction. These will provide potential targets for therapeutic intervention, as demonstrated by our work in the I L-2 pathway. (3) Experimental medicine. Complete our mechanistic investigations of the effects of IL-2 administration in patients, as a prelude to testing the efficacy of ultra-low dose IL-2 in the preservation of C-peptide and beta-cell function. Investigate, using the same mechanistic approach and depending on our emerging knowledge, another potential therapeutic.

Amount: £8,289,795
Funder: The Wellcome Trust
Recipient: University of Cambridge

A high resolution platform to capture the dynamic spatial proteome. 11 Jun 2015

This proposal aims to create a platform for mapping the subcellular location of a substantial proportion of the proteome in a single experiment with high resolution. It is based on preliminary work carried out by the Lilley group in collaboration with Thermo, giving tantalising insight into what this technology could deliver if developed further into a fit-for-purpose spatial proteomics platform. The key objectives are: 1. Expand the sampling of subcellular proteome to locate proteins to multi ple compartments. 2. Capture information of the effect of post-transcriptional and post-translational modification on spatial location. 3. Develop approaches to enable the mapping of the dynamic subcellular redistribution of proteins upon biological perturbation. 4. Incorporate work-flows that will deliver spatial information about targeted sub-sets of proteins and integration with whole cell maps. 5. Develop cross-linking strategies to preserve interactions of peripheral membrane proteins and between components of multi-protein complexes. 6. Develop a set of bespoke informatics tools facilitating the application of pattern recognition for robust analysis. 7. Create a GUI to facilitate community-wide interrogation of cellular maps. 8. Develop on-line protocols. 9. Apply the technology to the co-applicants and collaborators research, adding value to projects already funded by the Wellcome Trust.

Amount: £200,788
Funder: The Wellcome Trust
Recipient: University of Cambridge

New genetic, imaging and microfluidics technologies for single cell genomics 11 Jun 2015

Two major limitations of single cell genomics is (i) the loss of information about the original location within the sample of the sequenced cell and (ii) low throughput at high cost with only hundreds of cells analysed per day. Miniaturising single cell analysis to pico-litre volumes will critically facilitate higher throughput (10^4 - 10^6cells) at lower costs and sidesteps restrictions in handling. Combined with genetic technologies to record lineage history and spatially localise cells this w ill allow questions to be address at single cell resolution that are essential to understand cell diversification following tissue-contextual interactions and the impact it has on gene transcription. 1) We will develop microfluidics based devices to increase sequencing throughput by increasing the number of cells processed at a low cost, and at the same time enabling the complex handling and manipulation of small cell numbers with minimal loss. 2) We will develop genetic technology to: i) record within the genome the lineage history of each cell, for readout at any stage of interest and ii) to provide a unique fluorescent signature to cells to enable us to provide spatial and temporal context to their transcriptional profiles.

Amount: £410,687
Funder: The Wellcome Trust
Recipient: University of Cambridge

Construction and testing of a whole-cell arsenic biosensor with a simple visual readout for field use 29 May 2015

Arsenicosis from chronic consumption of contaminated ground water affects virtually all organs and tissues where skin lesions, bronchitis, gastroenteritis and ultimately a range of cancers are typical pathologies. Although arsenic contamination of drinking water is a global problem, it most seriously affects on the order of 100 million people in some of the poorest regions on earth including India/West Bengal, Bangladesh and Nepal. Prof James Ajioka's team at Cambridge University and Prof French at Edinburgh University are aiming to construct an inexpensive and reliable kit to assess arsenic contamination in drinking water in rural villages. Based on the observation that some bacteria detect arsenic, they will engineer an arsenic sensing device based on the Bacillus subtilis arsenic operon. This biosensor will be combined with a reporter system based on the violacein operon, resulting in bacteria that would turn green when it detects very low, safe levels of arsenic in the drinking water, but if the arsenic contamination is at a dangerous level, it will turn violet. The transcriptional signal to drive the pigment device in the bacteria can be tuned to respond to arsenic levels within definition of WHO safe or dangerous levels. The kit will be based on a weakened strain of the harmless soil dwelling bacteria, B. subtilis, housed in a robust plastic container to further reduce any risk and for easy, environmentally friendly deactivation/disposal.

Amount: £33,171
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2014 MPhil Appointments. 15 Dec 2014

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £28,140
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £7,750
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology - Sarah Foerster 30 Jan 2015

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £64,535
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology- Samuel Myers 30 Jan 2015

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £11,112
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology - Loukia Yiangou 30 Jan 2015

This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. Platform technologies supported by a Centre grant will en able SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploi ted to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem

Amount: £29,998
Funder: The Wellcome Trust
Recipient: University of Cambridge

2 month costed extension 20 Jul 2015

This application requests the continuation of core support to the Wellcome Trust/Cancer Research UK Gurdon Institute, which is an integral part of the University of Cambridge. The aim of the Institute is to contribute to an understanding of normal animal development, including the processes of cell differentiation, proliferation and morphogenesis, and to explain how cancers arise when these processes go wrong. The Institute sets out to achieve these objectives by recruiting excellent scientists and providing them with the best possible environment and facilities for their work. This is made possible by our core funding, which provides technical, administrative and secretarial support to our research groups, as well as expert assistance in bioinformatics, imaging and computing. Core support also ensures that our researchers have access to state of the art facilities, and we are requesting funding for advanced microscopy and high throughput sequencing equipment, and continuing support fo r our mouse facility. Our major goal for the next quinquennium is to produce world class research at the interface between developmental biology and cancer. To achieve this, we will increasingly use genome-wide approaches and quantitative proteomics, and we therefore plan to establish facilities for high throughput sequencing, high content screening, and mass spectroscopy

Amount: £339,619
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of TL1A-DR3 in immune complex-mediated autoimmune disease. 12 Jan 2015

In this project we propose to focus on the role of the DR3-TL1A axis in autoimmune disease and more specifically on its involvement in lupus nephritis. We will determine which subset of kidney-resident mononuclear phagocytes express TL1A following immune complex-dependent FcgammaR-cross-linking. We will also investigate the relative importance of DR3 expression on myeloid cells versus lymphocytes in disease pathogenesis. Finally we will address how the myeloid cells and lymphocytes interact in the kidney in vivo and determine the role of the DR3-TL1A axis in these interactions

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Virtual Fly Brain: a global informatics hub for Drosophila neurobiology 25 Jun 2014

Drosophila allows unprecedented genetic dissection of a relatively small nervous system that supports complex behaviours. Exploiting this opportunity requires intuitive tools to help users query the expanding knowledge from the literature and bulk image data, in order to generate hypotheses about neural circuits, and find reagents that target the neurons concerned. Virtual Fly Brain (VFB) is the only resource that provides this functionality,showing steadily increasing usage. We will further develop it, and lower the barriers for usersto find related Drosophila neuroanatomy and phenotypic information, and essential reagents, by: 1. Maintaining core coverage of literature and massively expanding bulk image data 2. Extending 3D image coverage to the whole adult and larval CNS 3. Increasing functionality of image, genetic, and phenotypic data available to users, including: - extending use of tools to predict overlap among neurons, structures and expression patterns - providing more comprehensive 2D and 3D image representations - allowing queries by behavioral and functional phenotype - providing access to electrophysiological data and circuit models 4. Increasing direct community input on the resource content, together with user annotation tools 5. Building a new web interface to provide intuitive navigation, including a more flexible and expanded query system

Amount: £141,493
Funder: The Wellcome Trust
Recipient: University of Cambridge

Enhancing the fission yeast model organism database POMBASE and extending the benefits of community annotation. 25 Jun 2014

Using Wellcome Trust funding, we have developed PomBase, a Model Organism Database to support exploratory and hypothesis-driven research using the model eukaryote Schizosaccharomyces pombe (fission yeast). To support literature curation, we have also developed a generic web-based, GMOD-compliant curation tool, Canto, which has been deployed to enable community-led curation, and a fission yeast phenotype ontology, FYPO. Here we request funding to sustain this important community resource by: 1. Curating and hosting newly published data. PomBase will continue to represent new data types, and to respond to evolving scientific approaches by developing new curation practices thereby benefitting fission yeast researchers and the broader scientific community. 2. Extending PomBase capabilities to satisfy specific future requirements, including: i) curation and display of multi-gene mutant phenotypes; ii) graphical display of modifications and mutations in sequence context; iii) enhancing gene pages to display concise textual and graphical annotation; iv) network and pathway data visualisation; v) an InterMine implementation for integration and analysis of complex biological data. 3. Extending the PomBase curation model to support Schizosaccharomyces japonicus and S. octosporus enabling researchers to reap the benefits of comparative genomic and functional analyses.

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

Function of GPR35 in inflammation 13 Nov 2013

G-protein-coupled-receptors play a major role in inflammation. Pepducins, short peptides coupled with a lipid moiety consciously designed towards the intracellular loops of GPCRs, are a novel approach for modulating GPCRs. They have both, utility for probing GPCR function and for developing novel therapeutics. GPR35, a receptor of unknown function, is activated by kynurenic acid, an end-product of L-tryptophan catabolism and 2-acyl-lysophosphatidic acid. Polymorphisms in GPR35 confer risk for ulcerative colitis and primary sclerosing cholangitis as revealed by genome-wide-association-studies. This proposal intends to address the role of GPR35 in inflammation. It rests on four major pillars: (1) Elucidation of GPR35 signal transduction and downstream biological consequences of receptor ligation. This will include the development GPR35-specific pepducins for the functional study of the receptor, and as novel therapeutics. (2) Interrogation of the role of GPR35 in inflammatory conditi ons in vivo. (3) Investigating the mechanistic consequences of the UC/PSC-associated GPR35 risk variant, through engineered variants, and in cells obtained from individuals with known GPR35 risk allelic status. (4) Investigation whether the pepducin strategy can be extended to pharmacologically correct altered GPCR function arising from genetic variants of GPR35. This may reveal novel precision medicines that target specific genetic variants.

Amount: £630,343
Funder: The Wellcome Trust
Recipient: University of Cambridge

Orientation of cell division in developing epithelia: molecular and physical mechanisms. 11 Aug 2014

My award aims at understanding the integration of cell intrinsic and extrinsicmechanisms during tissue morphogenesis. We use Drosophila embryos as a modeland focus our research on two fundamental and conserved morphogeneticphenomena: axis extension and compartmental boundary formation. Axis extensiontakes place during the gastrulation of all bilateral animals and similar morphogeneticmovements shape organs later in development. Partitioning tissues intocompartments that do not mix is essential for the correct morphogenesis of animaltissues.

Amount: £194,698
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring the roles of autophagy in the nervous system. 03 Oct 2013

Intracellular protein misfolding/aggregation characterises many late-onset neurodegenerative diseases, including Alzheimer s disease, Parkinson s disease, tauopathies, and Huntington s disease (HD)). The mutations causing HD and many related diseases confer novel toxic functions on the specific protein. Thus, it is important to understand the factors regulating the levels of these proteins. (Macro) autophagy clears long-lived proteins and organelles by forming autophagosomes that engulf p ortions of cytoplasm. Autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Autophagy regulates the levels of intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including HD. Autophagy upregulation may attenuate diseases like HD, and possibly tuberculosis. Autophagy inhibition slows growth of existing tumors, and may also contribute to pathology in various neurodegenerative diseases. I aim to: Discover novel autophagy-modulating dr ugs/pathways and test their clinical relevance in models of neurodegenerative diseases, tuberculosis and cancer. Test if there are beneficial/deleterious effects of constitutive autophagy upregulation in vertebrates. Develop methods to infer autophagic flux in vivo. Understand how autophagy compromise causes pathology. Identify novel autophagy-regulating mechanisms and investigate possible disease relevance. These studies will help the understanding of the relationship betwee n autophagy, normal physiology and disease, and will provide proof-of-principle for autophagy-modulating strategies as therapies for a range of conditions.

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

Immunogenetics of KIR and HLA-C variants in Ugandan women with disorders of pregnancy. 11 Aug 2014

We have shown that specific combinations of maternal and fetal immune genes predispose to reproductive failure. We will now identify the specific alleles that predispose to reproductive failure in humans. We will correlate, for the first time, maternal and fetal immune genotypes of large cohorts of normal and abnormal human pregnancies with blood flow dynamics at the experimentally inaccessible human maternal fetal-interface. Informed by these human genetic data we have designed experiments in mice to determine the downstream consequences of the interactions between maternal NK cell receptors (NKR) genes and fetal Major Histocompatibility Complex (MHC) genes on reproductive success. We will investigate in vivo exactly how these interactions control the mechanisms of vascular remodelling, placental development and fetal growth. A combination of cellular assays and transcriptome analysis will reveal the pathways activated in both maternal NK cells and fetal trophoblast cells upon int eractions with one another in both species. Bringing together human and mouse genetics, quantitative in vivo and in vitro assays and uterine

Amount: £231,840
Funder: The Wellcome Trust
Recipient: University of Cambridge