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Recipients:
University of Cambridge

Results

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

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

Developmental programmingof insulin resistance and obesity in offspring of diet induced obese mothers. 21 Feb 2011

To investigate the mechanisms involved in the developmental programming of obesity and insulin resistance in peripheral and central tissues of offspring of obese mothers using a mouse model of maternal diet-induced obesity.

Amount: £52,518
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evaluation of combinatorial drug strategies to combat de novo and acquired drug resistance to targeted molecular therapies. 20 Sep 2011

Cancer treatment with biological therapies has been limited by de novo and acquired resistance. The aim of the project is to utilise a screen of targeted combination agents across 1000 cell lines to discover novel synergistic therapies for the treatment of resistant cancer cell lines in melanoma and colorectal cancer. This project will primarily elucidate the functional biology of such synergy in the particular cellular contexts of BRAFmutant melanoma and colorectal cancer, and endeavour to utilise data from nextgeneration sequencing and gene expression to identify biomarkers for such treatments.

Amount: £223,979
Funder: The Wellcome Trust
Recipient: University of Cambridge

Quantitative proteomic analysis of latent human cytomegalovirus infection 25 Nov 2010

Following primary infection, HCMV typically establishes a latent infection in monocytes under the control of a healthy immune system. Little is known about the intracellular pathways manipulated by HCMV to maintain latency, or the phenotype of latently infected cells. I will: (i) identify cell surface targets of individual HCMV latency genes (ii) enrich ex vivo latently infected monocytes to characterise the most important biochemical pathways altered by latent HCMV infection. I have developed a new technique ?plasma membrane profiling? (PMP) to enrich plasma membrane (PM) proteins for proteomic analysis. I will employ the functional proteomics approach SILAC (Stable Isotope Labelling by Amino acids in Cell culture), to perform semi-quantitative analysis on plasma membrane proteins enriched by PMP. Using this approach I will determine how latent HCMV infection alters the cell surface proteome by analysing transduced cell lines expressing individual HCMV latency genes, and an in vitro model of latency. I shall use the markers I identify to enrich latently-infected ex vivo CD34+ monocytes. In addition, I will characterise biochemical pathways altered by latent HCMV infection in these cells using ?KAYAK? (Kinase ActivitY Assay for Kinome profiling), a novel proteomic technique. Candidate proteomic ?hits? will be biochemically characterised.

Amount: £243,917
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neuronal reward mechanisms. 02 Jun 2011

We investigate principal neurophysiological reward and risk functions during learning, decision-making under risk and social interaction in a variety of novel experiments using proven animal model methods. 1) We study subjective value and adaptive prediction error signals of dopamine neurons whilst learning stochastic rewards, experience reward contrasts and make risky decisions. We hypothesise that dopamine neurons track predicted values of choice options for decision-making under risk. 2) In frontal cortex, where lesions alter risk behaviour, we study how risk affects value coding, and we track the risk associated with choice objects and actions as important decision variable. 3) In a social setting, we study dopamine neurons and neurons in the striatum with convergent influences from different reward structures. We also investigate pro-social capacity for coordination and possibly cooperation, using procedures successful in birds. 4) We translate some of these studies to human imaging using the same behavioural tasks. These studies advance our knowledge on normal reward and risk processes underlying decision-making and extend this neurophysiology to humans to facilitate translational studies on patients.

Amount: £4,248,637
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of RNA turnover and processing. 09 Mar 2011

We will continue our investigations of structural and biochemical aspects of multi-component assemblies involved in post transcriptional gene regulation. We will build on our structural information to pursue biochemical and in vivo experiments that will help to explain how these assemblies function in their cellular contexts. The main topic of investigation is the bacterial RNA degradosome and its components, which we will further investigate as a model for global cellular regulation. We will co ntinue to obtain structural information on the degradosome, its subassemblies, and its cognate complexes with RNA substrates and regulatory non-coding RNAs, and we will build on this information to characterize the multi-faceted roles played by this machinery in the regulation and coordination of gene expression.

Amount: £1,250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional immunogenetics of fetal and placental development: the regulation of placentation by NK cell receptors and their trophoblast ligands 15 Mar 2011

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 artery Dopplers, this proposal is poised to generate data that will lead to new approaches for prevention and treatment of devastating conditions such as pre-eclampsia, recurrent miscarriage, fetal growth restriction and unexplained stillbirth.

Amount: £1,471,752
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structural analysis of Wntch signalling in Drosophila. 09 Mar 2011

Analysis of signalling during development has revealed a consistent and pervasive relationship between Notch and Wnt signalling suggesting that they form a single functional module. Notch encodes a member of a family of cell surface receptors that acts as membrane tethered transcription factors while Wnt represents a family of ligands that interact with receptors to modulate cytoskeletal activity and transcription. Work in Drosophila has revealed that Notch has the ability to modulate Wnt signal ling independently of its transcriptional activity and that this effect has an important function in processes of cell fate assignation. Our studies with Drosophila have uncovered an activity of Notch which targets the activated form of -catenin, the effector of the transcriptional activity of Wnt, and modulates its amount and activity. This function relies on the ligand independent traffic of the Notch receptor, provides a buffer for Wnt signalling and suggests a framework to think about Notch as a multifunctional receptor. Here I propose to probe the mechanisms that govern the interactions between Wnt and Notch signalling using Drosophila as a model system.

Amount: £344,942
Funder: The Wellcome Trust
Recipient: University of Cambridge

Reward prediction in health and disease. 21 Feb 2011

Our goal is to characterise and extend our understanding of behavioural and brain signatures of prediction-dependent responding in schizophrenia. The behavioural symptoms of schizophrenia, as well as the implications of dopaminergic alterations, suggest that abnormal prediction error signals and predictions may be key to understanding the condition. Several functional neuroimaging studies have provided evidence in favour of this view. However, the functions of prediction errors in learning and b ehaviour are complex and cannot be adequately characterised solely in terms of their presence and magnitude. We hypothesise that a detailed understanding of the adaptivity of prediction error coding and the variability of reward prediction in relation to background environmental characteristics will bring us closer to understanding the positive symptoms of schizophrenia. Our aims are therefore to explore these two features of error-dependent learning using complementary studies in control partic ipants and in patients with schizophrenia. Our specific goal is to identify changes in prediction error sensitivity to adaptation and contingency in patients and to characterise the extent to which these signals in healthy controls are susceptible to perturbations induced by dopaminergic drugs (L-Dopa and sulpiride). In doing so, we will provide critical insights to the neurobiology of positive symptoms of schizophrenia.

Amount: £381,826
Funder: The Wellcome Trust
Recipient: University of Cambridge

Human Monoclonal Antibody Therapy for Rhodesiense Sleeping Sickness. 05 Oct 2010

Human African Trypanosomiasis remains a serious health problem in Central Africa and treatment has been largely untouched by the advent of modern medicine. The chemotherapy used is based on drugs introduced between 40 and 90 years ago that have severe side effects including a few percent mortality. There is a desperate need for new medicines. Most trypanosomes cannot infect humans due to a primate-specific innate immunity mechanism based on apolipoprotein L-1 (apoL-1), a component of a subse t of high density lipoprotein (HDL) particles. Receptor mediated endocytosis of HDL and trafficking of the apoL-1 to the lysosome results in cell death. Trypanosoma brucei rhodesiense, one of the two human infective subspecies, counteracts the action of apoL-1 through the production of the SRA protein which binds to apoL-1 and prevents its action. The objective of this application is to produce and test a new therapeutic based on human monoclonal antibodies that bind SRA and block the bindi ng of apoL-1, thus rendering the trypanosome susceptible to killing by apoL-1. The use of human antibodies for the treatment of disease is an emerging technology that is characterized by dramatic on target efficacy, and little or no off-target effects.

Amount: £293,985
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

Pathways of CD4 T cell allorecognition in allograft rejection. 20 Jun 2011

Unique to transplantation, alloantigen originating from engrafted organs can be recognised by recipient CD4 T cells via two distinct pathways: the direct and indirect pathways. It is widely believed that the direct pathway is short lived due to rapid elimination of donor antigen presenting cells soon after transplantation, whereas the indirect pathway is long-lived. Additionally, there is some suggestion that direct pathway CD4 T cells can exert a cytotoxic effector function. These differences h owever, remain largely unproven. This project proposes to definitively characterise the indirect and direct pathways of allorecognition. The key goals include: - To definitively determine the relative duration of direct and indirect allorecognition by CD4 T cells. - To dissect out the role of donor and recipient dendritic cells in priming direct pathway CD4 T cells, and the role of NK cells in regulating the duration and magnitude of this recognition. - To examine the role of B cells in priming direct pathway CD4 T cells. - To provide a model for how late anti-MHC class II alloantibody arises. - To clarify the circumstances in which direct pathway CD4 T cells exhibit effector function and determine role of this in solid organ rejection.

Amount: £256,048
Funder: The Wellcome Trust
Recipient: University of Cambridge

Vaccination against gamma-herpesviruses. 26 May 2011

The gamma-herpesviruses are archetypal persistent parasites. Host immunity fails to prevent the long-term infectivity of virus carriers, presenting a major challenge to disease control. To make progress, we must use animal models to learn more about the fundamental biology of persistent infection. We want to know why virus-specific antibody, which neutralizes infectivity in vitro, fails to do so in vivo. If antibody could be made to neutralize secreted virions, viral transmission would cease.Mechanisms of immune control are difficult to analyze with human gamma-herpesviruses, so we are using the murid virus, MHV-68, to establish basic principles of gamma-herpesvirus infection control. Preliminary data indicate that truly neutralizing specificities are rare in the antibody response to MHV-68. Immune sera serve mainly to divert virions into cells bearing IgG Fc receptors, which then become productively infected. Virion / antibody complexes may even constitute the normal infectious particle.We will determine how rare, neutralizing monoclonal antibodies work, what happens to virion / antibody complexes in vivo, whether boosting the response to neutralization targets can increase the neutralizing activity of immune sera; and whether this improves infection control. We will then use the closely related Kaposi's Sarcoma-associated Herpesvirus, to adapt this experimental strategy of infection control to a clinical setting.

Amount: £268,073
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

Nanoscopy of Dynamics in the Living Cell. 12 Apr 2011

PrDramatic advances in several physics-driven laboratories have established the principle of super-resolution optical imaging. Major improvements in spatial and temporal resolution are sorely needed for the technology to be useful to answer major biological questions. We propose a bold multi-disciplinary program to drive the technology forward with biological applications that demand dynamic visualization on the nanoscale in the belief that step-change technology development cannot effectively e volve without motivation and pull from those who need the applications the most. Leveraging major investments made by Yale, we have assembled a multi-disciplinary team of engineers, physicists, and cell biologists from the Gurdon Institute, the Cell Biology Department at Yale, the LMB at Cambridge, and Oxford University which over five years will develop a new generation of microscopes and probes capable of multi-color dynamic imaging deep in live cells with spatial resolution

Amount: £701,155
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Cambridge-UCL Mental Health and Neurosciences Network. 12 Apr 2011

Our aims are to deconstruct current clinical classifications of psychiatric disorders and reformulate abnormal and disabling behaviours in terms of their underlying processing dimensions, based on a neuroscientific understanding of human brain development. We posit that a conventional psychiatric diagnosis is at best an epiphenomenon: the consequence of variability in multiple, developmentally-dependent dimensions of emotion, cognition, behaviour and their associated neurocomputational systems.. This radical and novel approach to characterising mental illness will be realised by defining population variation in key cognitive and behavioural phenotypes and linking these to underlying variation in the development of brain networks measured by structural and functional neuroimaging; the measured characteristics of these networks will be biomarkers for psychiatry. We will focus on the period of youth, 14 to 25 years of age, because this is a developmental epoch associated with major change s in normal cognitive function and brain organization, and (not coincidentally) with a high incidence of serious mental illnesses that continue through the rest of the life course: depressions, psychoses, conduct and personality disorders.

Amount: £5,386,687
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring the oligovascular niche in CNS remyelination. 19 Jul 2011

Remyelination is the process by which new myelin sheaths are restored to demyelinated axons. It involves the regeneration of new oligodendrocytes by a population of widespread multipotent adult neural stem cells called oligodendrocyte precursor cells (OPCs). There are three keys phases: first, OPC activation (initial critical changes in gene expression); second, OPC recruitment (proliferation and migration); third, differentiation into myelin-forming oligodendrocytes. Each stage is regulated by a complex interplay of environmental signals and cell intrinsic mechanisms. While many of the elements of this regulatory network have been explored the effects of the vasculature and especially new blood vessel formation remains unknown - a surprising gap given the role of angiogeneis in other regenerative processes and the proliferative effects of endothelial cells on OPCs in vitro. This one-year project will start with a description of the vascular changes associated with the remyelination of a well-characterized model of CNS demyelination using immunohistochemistry and transcriptome analysis, relating these to OPCs dynamics. It will end with a preliminary functional study on the OPCs effects of experimental manipulation of angiogenesis. The project is designed to provide grounding in laboratory-based neurobiology that will form the basis of further more detailed and technically demanding studies.

Amount: £62,740
Funder: The Wellcome Trust
Recipient: University of Cambridge