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Recipients:
University of Cambridge
Award Year:
2011

Results

Development of technology for combined PET and MR imaging. 30 Nov 2011

This research is centred on developments and improvement to a combined Positron Emission Tomography (PET) and Magnetic Resonance (MR) scanner that acquires images simultaneously and is dedicated to pre-clinical imaging. I will develop a volume RF transmitter system combined with dedicated receiver coils for MR, which will provide uniform excitation for all studies, with a consistent minimum degradation for PET detection. These structures need to be integrated with life support and monitoring equ ipment compatible with both the PET and MR environment. I plan to directly compare schemes for MR attenuation correction with that determined by a conventional rotating radionuclide source. The prototype scanner has access for a conventional transmission scan system that I propose to adapt to operate in the dual scanner. The aim is to directly measure the gamma ray attenuation for comparison with predictions based on MR image data. I will investigate the use of motion sensitive MR pulse se quences to record organ movement during the PET scan. Sequences will be tailored to periodically include motion sensing sections that can subsequently be used to determine organ position during PET reconstruction. The goal is to demonstrate that simultaneous MR acquisition can be used to improve PET reconstructed.

Amount: £88,624
Funder: The Wellcome Trust
Recipient: University of Cambridge

Enhancement: Interactions between the circadian clock and virus infection 06 Oct 2011

Daily (circadian) rhythms form a fundamental part of our existence, necessarily so because of our 24h solar environment. We know that the clock consists of an autoregulatory negative feedback loop involving various core clock genes. I seek to understand how the molecular clock affects neural processes to coordinate our rhythmic physiology and behaviour. Until now, addressing this question was not possible. With the recent advent of high-throughput tools to interrogate transcriptional contr ol, global gene expression and the proteome, it is now possible to tackle this problem in a molecular context. Expression of circadian genes starts with binding of transcription factors to DNA, then transcription of those genes into mRNA, and finally translation of this mRNA to protein. Each stage of this process will be interrogated, but in reverse order, starting with DiGE/iTRAQ to assay the proteome, expression microarrays (e.g. Affymetrix/Illumina) to look at transcript levels, and finall y ChIP-chip to address transcription factor binding to promoter regions of circadian genes. The interrelationships between DNA-mRNA-protein dynamics will be modelled using systems biology tools and bioinformatics to identify novel control points. A subset of the novel proteins will be functionally characterised to define novel circadian elements and/or targets for future therapeutic benefit.

Amount: £197,142
Funder: The Wellcome Trust
Recipient: University of Cambridge

Institutional Strategic Support Fund 2011/12. 17 Oct 2011

Support senior/leadership and early career recruitment in key strategic areas in the Schools of the Biological Sciences and Clinical Medicine Provide early career support for recently appointed lecturers, or equivalent, in the Schools of the Biological Sciences and Clinical Medicine Provide bridging support for early career scientists who are between awards Support capacity building in bioinformatics for translational clinical research Provide support for state-of-the-art Technology Platforms Strengthen links between the biological/clinical and physical sciences through internships for interdisciplinary research Strengthen links between biological/clinical sciences and the social sciences and humanities through support for policy workshops Support Public Engagement around key areas of our scientific research

Amount: £1,500,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of endogenous analgesia. 08 Dec 2011

The programme will address how two distinct mechanisms of endogenous analgesia control activity in the brainstem periaqueductal grey. I aim to provide an account in computational terms, in order to specify the precise decision algorithms (rules) by which they operate. First I address the mechanism by which predictions reduce pain, by exploring precisely what information within a prediction controls pain perception. Specifically, I will test Bayesian models against competing accounts. Brain i maging will be used to determine how this is implemented in forebrain structures, and if/how they modulate activity in the periaqueductal grey. Second, I address the mechanism by which escape under threat reduces pain. Here I propose a theoretical analysis of controllability in escape/avoidance learning, building on my existing Reinforcement Learning framework. I will implement evolutionary simulations designed to show whether pain modulation emerges as an intrinsic reward to guide escape. On the basis of this, I will test model predictions (behaviourally) and their implementation (using fMRI), using an active versus passive escape learning paradigm. Finally, I will use deep brain stimulation to provide convergent evidence of how these mechanisms depend on the periaqueductal grey, looking for a statistical interaction between stimulation and endogenous analgesia.

Amount: £722,829
Funder: The Wellcome Trust
Recipient: University of Cambridge

SOX2 and squamous lung cancer 08 Dec 2011

In the UK, squamous lung cancer (SQC) accounts for approximately 40% of cases. There is accumulating evidence that SOX2 may play a driving role in this common disease. This proposal will test the hypothesis that dysregulated expression of SOX2 is a critical event in the initiation and maintenance of squamous lung cancer (SQC). My aims are: 1. To establish the molecular context in which SOX2 dysregulation occurs in the pathogenesis of SQC. I have developed a unique, single molecule digital PCR protocol to facilitate a comprehensive and parallel survey of somatic copy-number variation and sequence mutations in microdissected archived precancer lesions. 2. To establish the effect of SOX2 dysregulation in an organotypic model of bronchial dysplasia. I will establish a 3-Dimensional organotypic model of bronchial dysplasia in which SOX2 overexpression can be reversibly activated, and the effect of this and potentially co-operating genetic lesions can be interrogated. 3. To develop a novel mouse model of SQC based on SOX2 dysregulation targeted to the basal stem cells of the adult mouse trachea. This state-of-the-art genetically engineered mouse will feature the ability to reversibly and sporadically activate SOX2 in the most plausible cell of origin of squamous lung cancer.

Amount: £875,280
Funder: The Wellcome Trust
Recipient: University of Cambridge

Oxygen sensing. 04 Oct 2011

Not available

Amount: £1,842,954
Funder: The Wellcome Trust
Recipient: University of Cambridge

Principles and programming of the mammalian germ line. 04 Oct 2011

Germ cells exhibit unique and comprehensive erasure and re-establishment ofepigenetic information, which is critical for totipotency and the transmission of geneticand epigenetic information with long-term consequences for subsequent generations1.The principles of germline biology have the potential to provide core knowledge for thecontrol and manipulation of cell fates in developing and diseased tissues.A clear understanding of the transient state of competence is required first, together withhow these primed cells respond specifically to the critical regulators of mouse primordialgerm cell (PGC) specification. Importantly, with germ cells we also have a uniqueopportunity to identify and understand how epigenetic regulators can systematicallyreset the epigenome, even of the somatic nuclei when exposed in oocytes.Understandably, we know least about the largely inaccessible early human germ cells(hPGC), but we have opportunities to establish credible in vitro models through inductionof competence in pluripotent and induced stem cells (hESC and hiPS) for the generationand systematic studies of hPGCs.Accumulation of genome scale information on early mammalian germ cells mightimprove the prospects for the integration and modelling of dynamic changes regulatingkey germline properties, and allow testable predictions about the performance of thiscrucial lineage. This may also help to build experimental models that mimic keygermline properties and through this, a route to the experimental manipulation of cellfates and physiology.

Amount: £2,936,640
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £515,052
Funder: The Wellcome Trust
Recipient: University of Cambridge

Establishing a healthy growth trajectory from birth: The baby milk trial. 07 Nov 2011

The prevalence of childhood obesity has increased rapidly over the past two decades. Excess weight in childhood tracks into adult life and causes problems both in the short term and in the long term. National surveys show that more than one in five children are already overweight (13%) or obese (10%) when they start school. Hence any efforts to prevent obesity must start early. The Foresight Report and the Healthy Weight Healthy Lives strategy have highlighted the importance of preventing childhood obesity by focussing on the early years. However, to date there is little evidence on which to develop effective preventive strategies. Infancy is a period of rapid growth and weight gain and obesity prevention during this period may be effective. Nutrition and growth during infancy may also have long term effects by altering eating behaviours and risks of obesity and obesity-related disorders in later life. UK Infant Feeding Surveys show that at birth one in three (35%) of babies receive formula-milk and this number increases to almost all babies (92%) at 6 months of age. Hence, in addition to promoting breastfeeding, it important to optimise the growth of formula-milk fed babies. Our previous research shows that parents who give their babies formula-milk as part of their everyday diet need more information and support. Researchers at the Centre for Diet and Activity Research (CEDAR) and MRC Epidemiology Unit in Cambridge have been working with mothers and healthcare professionals to develop a feeding programme which aims to avoid excess weight gain in formula-milk fed babies. The programme we have developed aims to support parents who feed their babies formula-milk to achieve a healthy pattern of growth and weight gain. The infant feeding programme will be tested in a randomised controlled trial involving 700 mothers and their babies. Half the mothers will be given advice and support to follow the new feeding programme. The other half will be given routine advice about formula-milk feeding and weaning. The growth of babies in the two groups will be compared. This comparison is important to test whether our new feeding programme is effective in preventing excess weight gain and subsequent obesity. The results of the study will help to inform infant feeding guidelines and will also help us understand the links between infant feeding, behaviour, appetite and growth.

Amount: £145,606
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigation of Metabolic and Growth-related Diseases Associated with Mutations in Phosphoinositide-3-kinase, Catalytic, Alpha Polypeptide (PIK3CA). 08 Dec 2011

Dysregulation of Type IA phosphatidylinositol-3-kinase (PI3K) signalling plays a critical role in both cancer and insulin resistance (IR). Yet how specificity of biological response to diverse stimuli is achieved by PI3K, and how this is perturbed in IR and related growth disorders, is not fully understood, in part because both knockout and transgenic overexpression of PI3K components perturb the stoichiometry of regulatory and catalytic subunits. Activating somatic PI3K mutations are commonly implicated in cancer pathogenesis, but have not been studied in isolation in human cells, while no unequivocal loss of function mutations in PI3K have been described to date. This project builds on recent work in the host laboratory on genetic disorders of AKT signalling by focussing on patients with rare functional mutations in the p110 catalytic subunit of PI3K, two in patients with severe IR, and one in mosaic form in a patient with unrestrained leg overgrowth. The project comprises compreh ensive genetic work up of these findings, metabolic study of the patients and relevant tissues, and signalling studies in dermal fibroblasts available for each patient exploiting state-of-the art techniques and a new collaboration, and permitting cell-based screening of potential therapeutic efficacy of a variety of pharmacological and genetic manipulations.

Amount: £212,922
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Role of DDX5 and DDX17 in the HIV-1 Life Cycle. 08 Dec 2011

HIV/AIDS has already, infected approximately 40 million people, and killed 20 million. Antiviral treatment is good however the virus mutates to evade both drugs and the human immune response. In Professor Lever's lab the interaction of the virus with the cell is studied and in particular how the virus uses cell factors to help assemble itself and export new viruses.The role of cellular RNA helicases in trafficking viral RNA through the cell has recently been under study and by extensive screenin g, DDX5 and DDX17 appear to be important candidates which have not previously been identified as involved in HIV infection.This study aims to assess their contribution. Since cellular proteins will not undergo mutational escape the parts of the viral RNA interacting with them must also be highly conserved and thus more vulnerable to therapeutic intervention. I plan to use a series of cell biological, biochemical, molecular biological and imaging techniques to confirm these findings and establish the specific stage of the virus lifecycle which is affected by knockdown of these proteins, and to evaluate where the interaction occurs within the cell. Ultimately, in collaboration with the Department of Chemistry, we aim to use small chemical substances to inhibit these interactions.

Amount: £191,193
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fragment-based approaches to the design of candidate drugs that interrupt protein-protein interactions involved in cell regulation 30 Nov 2011

The use of fragment-based drug discovery to identify novel drug candidates that modulate the BRCA2-RAD51 interaction for the treatment of cancerThe Trust has awarded over £2.4 million to Chris Abell, Tom Blundell, Marko Hyvonen, Grahame McKenzie and Ashok Venkitaraman at the University of Cambridge to use fragment-based approaches to design and make molecules that disrupt the interaction of two important proteins in human cells, the recombinase RAD51 and the product of the breast cancer-associated gene BRCA2.These proteins are involved in the repair of DNA breakage, and blocking their interaction should result in sensitization of cancer cells to DNA damage, e.g. by radiation, or directly induce cancer cell death during proliferation. Potent compounds will be developed by synergistic use of X-ray crystallography and synthetic organic chemistry, and improved in a highly focused way to make sure they are safe and suitable for development into possible drug candidates. The lead compounds will be tested against different cancer cell lines to identify susceptible cancers, the most probable therapeutic target being lung cancer. This funding follows on directly from a Translation Award to pioneer the use of fragment-based approaches against protein-protein interactions. That project established the use of biophysical methods, especially NMR spectroscopy and X-ray crystallography to identify fragments that bound at specific sites on a protein interface and to iteratively grow these fragments into successively more potent compounds.

Amount: £730,355
Funder: The Wellcome Trust
Recipient: University of Cambridge

Support for a Wellcome Trust / Academy of Medical Sciences Internship: Mila Roode 17 Oct 2011

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: £5,150
Funder: The Wellcome Trust
Recipient: University of Cambridge

Collagen Toolkits and related triple-helical peptides. 09 Mar 2011

We have synthesised Collagen Toolkits, two sets of ~60 triple-helical peptides comprising the entire triple-helical domain of collagens II and III. Using these, we map the binding sites of collagen-binding species to the collagens. This application seeks support to maintain and extend the Toolkits, allowing the scientific community better access to them, and from them to develop other standard ligands for collagen-binding materials. These and existing reagents will be distributed to commercial as well as academic laboratories. We have identified selective motifs for the collagen-binding integrins alpha1beta1 and alpha2beta1. We seek to extend this approach to alpha10beta1 and alpha11beta1. Similar work is in progress addressing the discoidin domain receptors, DDR1 and DDR2, and the immunoglobulin receptors, platelet glycoprotein VI (GpVI), LAIR-1 and OSCAR. Our project will culminate in the synthesis of specific ligands for each of these. Amongst extracellular proteins, we a re studying von Willebrand factor, fibronectin and several MMPs. We have requests from collaborators to study thrombospondins, LRR proteins such as decorin, and BMPs. We currently ship a GpVI-specific agonist, CRP-XL, to ~40 labs worldwide, and the alpha2beta1-binding peptide GFOGER to ~20 others. We seek to develop a range of reagents for the other species mentioned above.

Amount: £470,539
Funder: The Wellcome Trust
Recipient: University of Cambridge

High speed super-resolution imaging with the OMX microscope. 09 Mar 2011

The imaging of fluorescent proteins in living cells has proved a powerful approach in cell biology, but many processes cannot be visualised because of the limited sensitivity and resolution of current microscopes. We seek funding for an OMX imaging system that overcomes these limitations. The OMX has a simplified light path that makes it much more sensitive than standard microscopes, and is configured to image three wavelengths simultaneously. These increase the speed of time-lapse imaging by an order of magnitude, allowing the detection of faint, fast-moving fluorescent objects that are otherwise invisible. The greater sensitivity also allows the use of lower levels of illumination, which reduces photo-toxicity and photo-bleaching for long-term time-lapse imaging of light-sensitive samples. Another major innovation is the use of structured illumination to break the diffraction limit, doubling resolution to 110nM. The OMX can perform super-resolution imaging deep inside cells at several frames/second (unlike other super-resolution microscopes), and can therefore reveal dynamic features of subcellular structure at a new scale. This microscope will be a shared resource for all cell biologists in Cambridge, and will be used to investigate topics such as mRNA trafficking, neuronal polarity, the spindle checkpoint and DNA damage foci.

Amount: £784,137
Funder: The Wellcome Trust
Recipient: University of Cambridge

Upgrade of NMR Spectrometer Consoles to Secure the Future Operation of the Biomolecular NMR Facility in the Department of Biochemistry, University of Cambridge. 09 Mar 2011

We seek support for the replacement of our ageing 800 and 600 MHz NMR spectrometer consoles by the current state-of-the-art equivalent and to equip the latter machine with a high sensitivity cryoprobe. The NMR machines are part of the highly successful multi-user Biomolecular NMR Facility in the Department of Biochemistry. The shared facility is accessed by more than a dozen research groups who work on a wide range of biomedical projects. These are all related to the structure and function of mo lecules that are involved in fundamental roles in the diverse processes of life and through their dysfunction are related to disease. Many of the research projects studied in the NMR facility involve work with large proteins or multiprotein complexes, or comprise situations where the use of alternative structural methods such as X-ray crystallography is difficult. Our research covers topics that address elementary problems in biology, such as intra- and inter-cellular signalling, regulation of c hromatin structure, the biosynthesis of complex molecules such as antibiotics and molecular events that concentrate in, at or near cell membranes. Many of these research groups are supported by programme and project grants from the Wellcome Trust and include also a WT senior fellow.

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The anthropology of health in prehistoric Europe: a cultural history of variation, illness and death. 08 Jun 2011

This pilot research explores the medical anthropology of prehistoric Europe (40000 BC through the Classical era). Using a broad, systematically assembled range of published archaeological evidence (skeletal remains, art imagery and burials), it relates health to ways in which the body was defined, categorised, and acted upon culturally. For instance, it examines how death rituals responded to unusual health conditions in ways which might imply particular notions of good and bad deaths or social identities for the differently-bodied, how actual physical harm related to cultural symbolisations of violence, and how bodies were produced culturally through cosmetic, ritual or medical interventions. Large-scale patterns in health and the body, and case studies of particular interest and richness will be related to broader histories of social change; for instance, did the advent of sedentism and farming in the Neolithic or social hierarchies in the Iron Age not only change actual health but also affect how the body was conceptualised, gendered, harmed, healed and transformed at death? It will produce two key outputs: a general overview monograph exploring the prehistory of health in Europe, and a research report assessing the available data and exploring potential avenues for focused, major research projects.

Amount: £103,647
Funder: The Wellcome Trust
Recipient: University of Cambridge

An empirical base for understanding the early phase of the epidemiological transition: Short-term and spatial variations in infectious disease mortality in England 1600-1837. 08 Jun 2011

Omran's epidemiological transition from 'pestilences and famine' through a period of 'receding pandemics' has long been assumed to have been socio-economically, technologically and medically driven. In an English context limited success has been achieved in providing an effective epidemiological explanation for a diminution in the volatility of short-term death rates associated with infectious disease outbreaks. We will investigate to what extent different locations in England shared the sam e short term experience of mortality from c.1600 to 1837, as the nation transformed from a predominantly agrarian society to an increasingly urbanised and industrial one with an integrated transport system and growing international trading and migration flows. Using existing datasets of c.550 abstractions of individual parish burial registers (a 5 per cent sample of English parishes), we will consider whether mortality peaks and troughs coincided in different locations and whether synchronisati on increased over time. We will also aim to provide a firmer and detailed chronology for the divergence in the level and stability of adult and child mortality rates that is thought to have occurred in the early eighteenth century. We will trial similar analyses on later, Civil Registration-based data and develop more detailed age profiling using existing family reconstitutions.

Amount: £95,961
Funder: The Wellcome Trust
Recipient: University of Cambridge

The biology of DEXI a novel candidate gene in autoimmune disease. 19 Jul 2011

The autoimmune diseases type 1 diabetes (T1D) and multiple sclerosis (MS) have a strong genetic basis, and recent genome-wide association studies have revealed many shared genetic risk variants, including the 16p13 region. Within this region, we have identified the DEXI gene, of unknown function and with no paralogue elsewhere in the genome as the most likely causal variant in autoimmune disease risk. The T1D and MS associated SNPs in the 16p13 region are eQTLs for DEXI expression in 2 independe nt monocyte data sets, and we have also shown their physical association with the DEXI promotor region by chromosome conformation capture. My future goal is to understand the biology of DEXI and its role in autoimmune disease pathogenesis. Key goals: 1. To evaluate changes in DEXI expression by qPCR in different stimulation conditions using cell lines, human monocytes and CD4+ cells 2. To develop a monoclonal antibody to DEXI to allow localisation of the protein within cells, quantificatio n of protein and to assist with the identification of binding partners of DEXI 3. To examine changes in immune cell gene-expression profiles by microarrray following over-expression and knockdown of the DEXI gene 4. To make recombinant DEXI and identify binding partners of this protein

Amount: £423,781
Funder: The Wellcome Trust
Recipient: University of Cambridge

Normative neurophysiology. 10 May 2011

Not available

Amount: £989,211
Funder: The Wellcome Trust
Recipient: University of Cambridge