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Award Year:
2011
Recipients:
University of Cambridge
Currency:
GBP

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

Oxygen sensing. 04 Oct 2011

Not available

Amount: £1,842,954
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £515,052
Funder: The Wellcome Trust
Recipient: University of Cambridge

Function and evolution of the atypical Notch ligands Dlk1 and Dlk2 during vertebrate development. 31 Aug 2011

Delta-like homologue 1 (Dlk1) is a vertebrate-specific atypical Notch ligand involved in development of multiple lineages in mouse. Genetic studies have shown it to be a key regulator within several pre and postnatal stem cell niches. Murine Dlk1 encodes soluble or membrane-bound protein isoforms depending on the presence of a juxtamembrane protein cleavage site, removed inalternatively spliced transcripts. Deciphering the signaling mechanisms of Dlk1 and the different functions of the Dlk1 isoforms has been very challenging in mouse. Zebrafish (Danio rerio) is an ideal model system to elucidate the fundamental aspects of Dlk1 function due to the relative ease and availability of molecular tools and techniques. In addition, Dlk1 in zebrafish is missing the juxtamembrane motif, whereas a closely related vertebrate-specific gene Dlk2, retains it, suggesting that zebrafish may use adifferent mechanism to produce membrane-bound and soluble Dlk, fulfilled by Dlk1 and Dlk2 respectively. Such proposed gene-specific functions make zebrafish a tractable model to decipher the specific roles of the secreted and

Amount: £155,658
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional comparative studies of cerebral cortex development using pluripotent stem cells. 31 Aug 2011

The cerebral cortex is the part of the central nervous system essential for higher brain functions such as sensory perception, cognitive function and consciousness. The human cortex is unique in terms of its enlarged surface area, expanded volume and a greatly increased number of cortical neurons. In contrast, the size of the cortex is markedly smaller in a human genetic neurodevelopmental disorder, primary microcephaly. We propose to use stem cell models to investigate the genetic control underlying the increased size and complexity of the human cerebral cortex. Specifically, we will focus our analysis on neural stem/progenitor cells.

Amount: £155,658
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigation of the mechanisms used by Vaccinia virus protein C6 to modulate the host immune response and contribute to virus virulence. 12 Jul 2011

This project aims to understand the mechanisms used by Vaccinia virus (VACV) protein C6 to modulate the host immune response. Specifically, how C6 inhibits type I interferon (IFN)- induced gene expression, the function of the interaction between C6 and the cellular protein SMARCc1, and the contribution of different C6 interactions to virulence in vivo. The subset of IFN-induced genes whose expression is altered by C6 will firstlybe determined. Key events in the signalling pathway required for the IFN-dependent induction of gene expression will be analysed in the presence of C6 to determine where inhibition by C6 occurs. SMARCc1 is a component of the mammalian SWI/SNF complex involved in chromatin

Amount: £155,810
Funder: The Wellcome Trust
Recipient: University of Cambridge

Identification of novel gd T-cell ligands cells using a forward genetic screenin haploid human cells. 12 Jul 2011

ãä T cells are a unique subset of T cells which do not require antigen processing and subsequent presentation by major histocompatibility complex (MHC) molecules, but instead recognise antigens directly. However, very little is known about the mechanisms of ãä T-cell ligand recognition. Therefore, we propose a novel gene-trap mutagenesis approach in human haploid cells to identify novel ãä T-cell ligands. There are four primary objectives that need to be met to carry out a successful screen using human ãä T cells and the near-haploid KBM7 cells: (i) establish specific ãä T-cell lines of interest; (ii) prove susceptibility of KBM7 cells to lysis by the particular ãä T-cell subset; (iii) mutagenise the KBM7 cells and

Amount: £155,810
Funder: The Wellcome Trust
Recipient: University of Cambridge

Application of ribosomal profiling to investigate established and novel translational control phenomena in viruses 12 Jul 2011

Historically, studies of gene expression have measured mRNA abundances rather than rates of protein synthesis. RNA expression profiling techniques, including microarray analysis, have revolutionized our ability to monitor the internal state of cells; however, mRNA and protein levels are often imperfectly correlated, and translational control can have a crucial role in modulating gene expression. In 2009, Ingolia and colleagues described ribosomeprofiling, a technique that provides global analysis of ribosomal footprints on mRNAs, providing new insights into translational control. Together with thelatest advances in deep-sequencing, ribosome profiling can provide a high resolution map of the location of translating and paused ribosomes on the transcriptome at any one time. Ribosomal profiling has since been used to study a variety of translational processes through the definition of ribosomalpause sites, inevitably revealing novel coding sequences. However, profiling is yet to be applied to the study of the regulation of virus gene expression. We will use ribosome profiling to investigate (1) ribosomal pausing at sites

Amount: £155,810
Funder: The Wellcome Trust
Recipient: University of Cambridge

Novel strategies using 'biased' agonists at the apelin receptor for the tratment of cardiovascular disease 12 Jul 2011

Pulmonary arterial hypertension (PAH) is a fatal disease caused by genetic mutations in BMPR-II, or drugs and toxins such as monocrotaline (MCT). We hypothesize this combination of afterload reduction and positive inotropy caused by apelin, the endogenous ligand of the APJ receptor, may be beneficial to PAH. MM07, a synthetic apelin analogue and a biased agonist of APJ, is highly potent in functional assays and less likely to desensitize APJ. Preliminary results indicate that MM07 is stable in vitro and safe in vivo. Our main objective is to study the effects of apelin in animal models of PAH, and in cultured cells. Using the MCT-treated rat meodel, the ability of MM07 to prevent and reverse PAH will be tested. Then the effects of APJ agonism will be confirmed using a competitive antagonist. Additionally, MM07 will be tested in another animal model with a BMPR-II mutation. A non-peptide APJ agonist may also be used to prevent PAH. Furthermore, alteration of the apelin/APJ system will be investigated in vitro in cells from PAH patients. The consequences of these changes and connections with the BMPR-II pathway will be explored. Our findings may support the use of APJ agonists in cardiovascular diseases like PAH.

Amount: £155,834
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating changes in hypothalamic gene expression that underpins the loss of counter regulatory defences to hypoglycaemia. 28 Mar 2011

Line 1: To identify changes in hypothalamic gene expression that underpin the loss of critical, defensive counter-regulatory responses to hypoglycaemia in type I diabetes mellitus. Line 2: To examine in greater depth the molecular mechanisms identified in line 1, to determine the pathophysiological basis for loss of hypoglycaemic counter-regulation in diabetes. Line 3: To predict and analyse potential therapeutic manipulations of counter-regulatory defences to hypoglycaemia based on pathways identified in line 2 in an animal model of diabetes.

Amount: £49,916
Funder: The Wellcome Trust
Recipient: University of Cambridge

The reprogramming of sperm compared to somatic celi nuclei. 17 Jan 2011

The sperm cell has a highly specialised developmental programme and gene expression profile. However, in order to allow embryo-specific gene expression, the paternal genome has to undergo reprogramming. Reprogramming is also crucial for a proper embryonic development during another process -somatic cell nuclear transfer (SCNT). Normally, a cell once differentiated, cannot de-differentiate. However, it has been shown that it is possible to de-differentiate a cell experimentally. When somatic cell nuclei of Xenopus laevis were transferred into enucleated eggs, healthy embryos were generated. However, in contrast to fertilization, SCNT seems to be significantly less efficient in embryo generation [1]. But can mechanisms of reprogramming after fertilisation be directly compared with those that follow SCNT? Probably not, as both processes occur differently. In order to investigate the comparative efficiency of fertilisation events and SCNT in offspring generation, I would treat the sperm in the same way as the somatic cell is treated in the SCNT procedure and examine the developmental capacity of such embryos. If the results prove that the sperm is indeed more efficient than a somatic cell nucleus in producing normal embryos, I would investigate what is so special about the sperm making it so efficient. This would lead to an identification of sperm-specific factors responsible for the efficiency of the reprogramming after fertilization. Ultimately, further characterisation of these factors and mechanisms of their action should shed light on similarities/differences between reprogramming after fertilization and SCNT. It would be a major contribution to understand what controls the ability, especially of nuclei from differentiated cells, to lead to normal embryo development.

Amount: £29,661
Funder: The Wellcome Trust
Recipient: University of Cambridge

Allergen like molecules in Schistosoma haematobium: roles in human immunity and acute disease. 31 Aug 2011

This project will be the first systematic study of 1111tigenic proteins from Schistosoma haematobium, a major helminth pathogen of man. lgE-mediated immune mechanisms are central to immunity to parasitic worm infections and allergy. Recombinant forms of S. haematobium Tegumental Allergen-Like (ShTAL) proteins will be used to characterise patterns of anti-ShTAL lgE responses and IgE-mediated effector functions in human cohorts living in S. haematobium endemic areas of Mali, and in travellers returned to UK with recently acquired infections. These data will be analysed in relation to human susceptibilitY and immunity to infection, the regulation of human IgE and lgE-mediated effector mechanisms, and acute and chronic schistosomiasis morbidity. Specific aims: To identify tegumental allergen-like (TAL) proteins in S. haematobium using adult worm and egg EST databases. To create expression profiles of S. haematobium TALs (ShTALs). To express and purify recombinant ShTAL proteins. To establish patterns of antibody isotype responses to these ShT ALs in human sera collections from studies in aS. haematobium high transmission area of Mali. To test the ability of individual ShTALs to trigger human lgE-dependent immune effector mechanisms. To analyse anti-ShTAL antibody isotype responses in relation to age, sex, intensity of infection and the effects of chemotherapy. To analyse antibody isotype responses to the ShTALs (and circulating cytokine levels) in relation to human immunity, reinfection and urogenital morbidity. To analyse anti-ShTAL IgE and IgG subclass antibody responses and passive and active histamine release, in travellers returned to UK with S. haematobium infection.

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

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. 20 Sep 2011

Evidence suggesting a link between iron status and type 2 diabetes (T2D) comes from meta-analyses of observational studies showing consistent associations between higher ferritin levels, the main marker of body iron status, and T2D. In addition, secondary diabetes is a common manifestation observed in patients with hemochromatosis, a hereditary disease characterised by extreme iron overload. Iron status is a modifiable factor, and hence presents a potential target for the prevention and treatment of T2D. However, important questions regarding the causal nature and sequence, as well as the mechanisms underlying the association between iron status and T2D remain unanswered. Genetic determinants of iron status may help to address some of these questions, but have not been systematically identified in adequately powered studies. This PhD will study determinants and consequences of differences in iron status using detailed phenotypic and genotypic information from large scale population studies of T2D, including almost 70,000 individuals, to assess whether and how iron status may causally affect T2D risk.

Amount: £358,433
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wolbachia as a defence against RNA viruses in insects. 07 Mar 2011

The bacterial endosymbiont Wolbachia protects insects against viral infections. The aim of this project is to understand this new form of antiviral protection, using Drosophila as a model system. Our results will be relevant for attempts to use Wolbachia to control viral diseases of humans and animals that are transmitted by insect vectors. To understand the causes of this antiviral resistance, we will first determine which stage of the viral replication cycle Wolbachia affects (entry into ce lls, replication, translation or exit). In Drosophila, we will screen for host genes and pathways that are required for the antiviral effects of Wolbachia and examine whether the antiviral protection relies upon the insect immune system or other host pathways. From the bacterium s perspective, we will identify Wolbachia genes up-regulated upon host viral infection and test these for their antiviral effects. Additionally, we will use next-generation sequencing to identify genes associated with n aturally occurring variation in the antiviral properties of Wolbachia. Finally, to see if interventions using Wolbachia will be sustainable, we will test whether viruses can evolve to overcome the antiviral effects of Wolbachia and identify the mutations that underlie these changes.

Amount: £548,004
Funder: The Wellcome Trust
Recipient: University of Cambridge

The influence of intracellular bacteria on MHC class II in relation to autoimmunity . 07 Mar 2011

MHC class II molecules, which present peptide antigens to T-cells, are associated with autoimmune disease, by mechanisms that are incompletely understood. A set of autoreactive T-cells that escape thymic tolerance and induce autoimmune disease has been identified. These Type B T-cells respond to peptide antigen but not to antigen derived by processing in the conventional class II pathway, which supplies antigen to Type A T cells. We have demonstrated that intracellular Salmonella interfere w ith MHC class II presentation, leading to partial loss of mature class II from the cell surface. We propose to investigate whether the disturbance in MHC class II by Salmonella leads to skewing in presentation of self-epitopes to Type B T-cells. We will ask whether Salmonella influences the loading of antigen in early and late compartments. This approach will be supported by investigation of the precise molecular mechanism of MHC Class II down-regulation. In addition, we intend to use a powerful mutant screen to identify genes required for presentation to Type A or Type B T-cells. These experiments would have consequences both for the way in which Salmonella manipulates the immune system as well as understanding of autoimmunity.

Amount: £244,819
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms of filopodia formation. 22 Jun 2011

I have developed a reconstitution system using supported lipid bilayers and Xenopus egg extracts that recapitulates several aspects of filopodia formation in a format highly amenable to microscopy and intervention. The filopodia-like structures are comprised of long, parallel bundled actin filaments that polymerise from the membrane surface. At the membrane there is assembly of actin regulators that mimics the filopodial tip complex. To understand how the tip complex functions I propose to: (1 ) determine the assembly mechanism of the tip complex. I will do this by (a) measuring the recruitment of proteins to the tip complex (b) studying the roles of tip complex members toca, IRSp53, srGAP2 (of the BAR domain superfamily) and Cdc42 (the Rho-type GTPase) in initiation using mutant proteins, immunodepletion and kinetics using fluorescent probes and (c) testing the contribution of Ena/VASP/Evl and diaphanous-related formins using similar techniques; (2) explore the molecular architecture of the tip complex using single molecule microscopy to determine the relationship between the structure and function of the tip complex; (3) compare the kinetics of protein recruitment to filopodia formed during early development to determine whether the molecular mechanism is conserved between different cell types.

Amount: £1,168,078
Funder: The Wellcome Trust
Recipient: University of Cambridge

Complementary studies of learning and motivation in psychosis and pathological hyperphagia. 26 May 2011

The proposal is based on the hypothesis that psychosis and pathological hyperphagia may be understood in terms of differing perturbations within reinforcement learning circuitry and that parallel explorations of these perturbations will generate complementary insights both to the conditions themselves and to the neurobiology of reward processing generally. The following are the key goals: To conduct parallel clinical and normative studies leading to a detailed understanding of how primary ( food) and secondary (financial) rewards, as well as environmental predictors of those rewards, are associated with deranged (psychosis) or enhanced (MC4R deficiency) motivation and responding. To further our neural understanding of these two serious health problems and, in doing so, enhance knowledge of how and why humans respond to reinforcing stimuli. To gain insights into how reinforcement learning circuitry is integrated with endocrine and metabolic signals, elucidating the ways in whi ch these signals translate into complex behaviours including attention, motivation and learning. To examine general motivational disturbances in psychosis under different circumstances (early onset psychosis, established psychosis, ketamine-induced psychosis) and to extend this to examine food-related motivational changes pertinent to the eating and metabolic changes found in association with schizophrenia and antipsychotic treatment.

Amount: £998,974
Funder: The Wellcome Trust
Recipient: University of Cambridge

Detecting treatment response in cancer using hyperpolarised magnetic resonance imaging (MRI)Patients with similar tumour types can show very different responses to the same therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment. 12 Apr 2011

Conventional Magnetic Resonance Imaging (MRI), which produces images of tissue morphology by mapping the distribution of water molecules, can be used to detect tumours and monitor their responses to treatment by measuring reduction in tumour size. However, changes in tumour size may take many weeks to become manifest, and with some treatments may not occur at all despite a positive response to treatment. MRI can also be used to detect tumour metabolites in vivo, using magnetic resonance spectroscopic imaging techniques. However, these metabolites are present at ~10,000x lower concentration than tissue water, which makes them hard to detect and difficult to image, except at relatively low resolution. Professor Kevin Brindle and his colleagues in Cambridge have been developing a technique in collaboration with GE Healthcare, termed “hyperpolarisation”, which increases the sensitivity of MRI by 10,000 – 100,000x. With this technique they inject a hyperpolarised 13C-labelled molecule and now have sufficient sensitivity to image its distribution in the body and the distribution of the metabolites produced from it, effectively providing a real-time readout of tissue metabolism. They have shown, in preclinical studies, that they can detect very early evidence of treatment response in tumours by using this technique to monitor changes in tumour metabolism. The team have been awarded ~£4.3M of translational funding to take this technology from the laboratory to the clinic, where they will investigate its potential for detecting early evidence of treatment response in lymphoma, glioma and breast cancer patients.

Amount: £4,284,278
Funder: The Wellcome Trust
Recipient: University of Cambridge