- Total grants
- Total funders
- Total recipients
- Earliest award date
- 23 Jan 2012
- Latest award date
- 18 Dec 2012
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
My laboratory investigates the molecular mechanisms that control the 24 hour (circadian) clock. This fundamental process is integral to the function of all cells. Our recent work has highlighted a critical role for a family of proteins called peroxiredoxins in the clockwork, and has shown that redox oscillations in mammalian cells contribute significantly to a cell's rhythmic properties. A Senior Fellowship would allow me to examine how the clockwork functions in 'real-time', using a variety of novel tools that we are developing to do this. We will also perturb redox pathways (that normally get rid of harmful oxidants produced because of respiration) and investigate the effect of this on the clockwork using these tools. A final goal will be to integrate redox oscillations with existing components of the clockwork, which rely on the process of gene transcription to work. The goal is therefore to fully characterise the mechanism of how a cell keeps time, particularly with respect to redox metabolism, which is a new and exciting area of study within the field.
The Diagnostic and Statistical Manual of Mental Disorders is the standard reference for the classification of mental disorders, and is seen as authoritative by clinicians, academics, drug companies and policy makers alike around the world. As the first major revision since 1994, the publication of the upcoming 5th edition of the DSM in May 2013 will represent a significant social and medical event. Psychiatric discourses have increasingly struggled with their embeddedness in culture since the pa rtial declassification of homosexuality from the DSM in the 1970s. DSM-5 has responded to this predicament through the proliferation of ever more precise labels. Against this backdrop, the fundamental question that our conference aims to explore is: how do changing classifications of sexuality and gender in DSM-5 navigate wider cultural discourses about morality and human nature? Our conference will bring together an interdisciplinary range of scholars: members of the DSM-5s Sexual and Gender Id entity Disorders Work Group, mental health practitioners, activists, sociologists, political scientists, ethicists, historians and philosophers. We aim to generate new conceptual and substantive work on the interaction between psychiatry and culture, pioneering analyses of the sexual classifications produced by DSM-5, which are expected to be used globally for decades to come.
Institute of Metabolic Science. 12 Oct 2012
With support from the Wellcome Trust and MRC, we have established an internationally leading Institute for Metabolic Science (IMS) in Cambridge. The world-class investigators we have assembled, combined with the excellent facilities we have established, have brought us within sight of our goal to translate advances in the understanding of basic mechanisms involved in obesity, diabetes and related metabolic diseases into benefits for health. In this proposal, we seek support for: 1. The co nstruction of a dedicated Metabolic Clinical Research Facility (MCRF) and Eating Behaviour Unit (EBU) to support the expansion of translational research programmes and capitalise on local strengths in the basic and clinical neuroscience of appetitive behaviour. 2. A collaborative programme with the Wellcome Trust Sanger Institute in the generation and phenotyping of murine models of metabolic disease. 3. Improved cell imaging and proteomic facilities in collaboration with the Cambridge Ins titute for Medical Research (CIMR). 4. Equipment to update our core Genomics/Transcriptomics laboratory We have been encouraged to submit a complementary bid to the MRC and further support is being provided by the University of Cambridge. If awarded, these additional resources will significantly enhance our abilities to conduct the highest level basic and translational science in metabolism.
InterMine and humanMine - enhancing the biomedical relevance of model organisms and enabling other data mining projects. 22 May 2012
Five of the major Model Organism Databases (MODs) have adopted the InterMine data integration platform to provide flexible searching and data mining interfaces to their user communities, the first time these widely used resources have converged on a common software platform. Furthermore InterMine is becoming established as a major platform for data integration by other projects. A challenge for modern biology and a key aim of the MODs in using InterMine, is to promote interoperability and cro ss organism integrative analysis. A unique opportunity exists to create a human InterMine resource that, via the same mechanism of inter-operation, will provide uniform medically relevant human data to model organism research communities. Simultaneously the biomedical research community will gain simple access to the wealth of model organism research. We request 5-year support (1) to maintain and develop the core InterMine infrastructure on which the above projects depend, including devel oping MOD/human integrative analysis tools; (2) to build and maintain an integrated human InterMine database with which the MODs and other users can interoperate. These developments will have an impact by facilitating the research carried out by the thousands of MOD users worldwide and also users of other InterMine-based databases.
Translating whole genome sequence technology into diagnostic and public health microbiology 27 Apr 2012
Effective mechanisms of surveillance are required to track disease trends, identify new infectious disease threats, detect serious outbreaks, monitor control measures, design effective vaccines and monitor for vaccine escape. The present public health system falls short of what is required because of a technology gap whereby it is not possible to make rapid or in some cases accurate inferences regarding pathogen outbreaks and transmission events using the currently available microbial genotyping methodology.Through this award to Cambridge University, Professor Sharon Peacock will seek a solution to this need through the development of a world-class system of active surveillance based on microbial whole genome sequencing (WGS), in collaboration with the Cambridge University Hospitals NHS Trust, the Health Protection Agency and the Wellcome Trust Sanger Institute. The aim is to embed a genome sequence-driven microbiology initiative within a clinical campus, working alongside a hospital diagnostic and public health laboratory. Key objectives are to understand how to apply genomics to address the problems of infectious disease control scaled to local, regional or national levels, and how to integrate this technology into on-going practice so as to expand and enhance the current system of infectious diseases surveillance conducted.
Future Families: The social and psychological outcomes of emerging assisted reproductive technologies for individuals, families and society. 31 Jan 2012
Advances in assisted reproductive technologies in combination with recent legislative changes are giving rise to new family forms that would not otherwise have existed such as gay fathers with children born through surrogacy and egg donation; single mothers by choice who conceive their children by donor insemination and intentionally parent alone; and donor siblings who are conceived using the same donor but raised in different families. Moreover, a growing number of families are being created t hrough egg sharing, egg freezing, and intra-family donation, with artificial gametes on the horizon and UK donor-conceived offspring entitled to request their donor's identity in 2023. Although there is concern about the potentially adverse social and psychological consequences of these new practices and procedures, this is based on speculation and assumption rather than systematic study of actual outcomes. The aim of the proposed research is to obtain empirical data on the impact of advances in assisted reproduction as they emerge in order to address the ethical issues that they raise and inform the development of policy and practice from the outset. The overarching question to be addressed is What are the social and psychological outcomes of emerging assisted reproductive technologies for individuals, families and society? Given that 4.5 million children worldwide have been born through assisted reproduction, with the number increasing exponentially each year, the proposed research has the potential to make a significant contribution internationally to public debate, clinical practice and regulation in this controversial yet expanding area of public health.
Hormone release from the gastrointestinal tract: mechanisms underlying bile acid-induced GLP-1 release and characterisation of somatostatin signalling. 25 Jun 2012
Gut hormones are key to the regulation of nutrient homeostasis and therefore particularly relevant to type-2 diabetes. This proposal involves determining the mechanisms underlying secretion of two gut hormones, glucagon-like peptide1 (GLP-1) and somatostatin (SST). GLP-1 is an incretin hormone released in response to components in the intestinal lumen and acts to support nutrient disposal throughout the body. A preliminary project recently identified a G-protein coupled bile acid receptor(GPBA)-independent signalling pathway of bile acid-induced GLP-1 secretion in the distal small intestine. This study proposes to characterise this pathway and determine the roles of apical sodium-dependent bile acid transporter (ASBT) and farsenoid X receptor (FXR) in vitro and in vivo using appropriate inhibitors/agonists and knockout mice. An investigation into the relatively poorly understood inhibitory gut hormone SST is also proposed. SST negatively regulates the secretion of many hormones including GLP-1 but the stimuli and signalling pathways by which SST release occurs are poorly characterised. This proposal involves in vitro assessment ofSST secretion in response to various nutrients and pharmacological tools as well as the relationship between SST and other gut hormones. These data, together with transcriptomics of SST-producing cells, will be used to identifycell-specific signalling pathways.
Innate memory: What is the biological significance of memory NK cells in infection and cancer? 27 Jan 2012
Our goal is to study the newly discovered ?memory? NK cells. The three main aims are: 1. Define their lifespan and effector functions 2. Determine their biological significance in viral infections and cancer 3. Characterize their transcriptome
The first part of the project will be to validate the existing transcriptomic data regarding chemokine receptor expression by FAP+ cells in tumour and peripheral tissues. Tissues will be collected and digested to obtain single cell suspension, they will then be stained for FAP expression and sorted by FACS before mRNA analysis by qRT-PCR. Protein expression of CXCR7 will also be examined by flow cytometry and histology. Once chemokine receptor expression has been confirmed, function will then be analysed. Preliminary data suggest that there is little turnover of FAP+ cells within the tumour microenvironment (Kraman & Fearon, unpublished data); however as the tumour grows, the proportion of resident FAP+ cells remains constant. It is therefore possible that FAP+ cells from peripheral sites populate the tumour. FAP+ cells from the subcutaneous LL2/OVA tumour produce high levels of SDF-1 (Roberts, Kraman and Fearon, unpublished data), and it has been demonstrated in humans that serum SDF-1 can become elevated in cancer patients (Woo et al. 2008, Macoska et al. 2008) and inflammation, including pre-eclampsia (Schanz et al. 2011), Duchenne muscular dystrophy (Abdel-Salam et al. 2010), burn injury (Drukala et al. 2011) and stroke (Paczkowska et al. 2009). This may therefore be a mechanism by which FAP+ cells are recruited to sites of tissue injury. Haematopoietic stem cells are maintained in the bone marrow by interaction between CXCR4 and SDF-1 (Ma et al. 1999), if interrupted by treatment with AMD3100, reversible release of CD34+ haematopoietic stem cells occurs (Liles et al. 2003). By analogy, it is possible that CXCR7 plays a role in the retention of FAP+ cells in the tissues by interaction with matrix-bound SDF-1 and that in an environment with high circulating levels of free circulating SDF-1, this retention is out-competed. In order to investigate this, serum levels of SDF-1 will be examined by ELISA in tumour bearing KPC mice and compared to non-tumour bearing counterparts and littermates lacking one of the three KPC mutations (Hingorani et al 2005). It has been shown in a model of acute liver failure that intraperitoneal injection of SDF-1 promotes migration of bone marrow mononuclear cells to the liver (Jin et al. 2009). Should SDF-1 levels be raised in the KPC mice, this data will be used to inform a subcutaneous osmotic pump, which will deliver a dose of SDF-1 sufficient to maintain the same serum level; the question may then be asked as to whether high circulating SDF-1 can recapitulate the cachectic phenotype observed in tumour bearing mice. Mobilisation or death of FAP+ cells will be analysed by flow cytometry and histology of tissues in combination with analysis of FAP+ cell numbers in peripheral blood. If they are found to be mobilised, a subcutaneous matrigel plug either injected with SDF-1 or surrounding the osmotic pump could also be used to trap and identify any cells migrating toward the chemokine gradient. Given that SDF-1 is also the ligand for CXCR4 (Bleul et al. 1996, Oberlin et al. 1996) specific blockade of CXCR7 is required to understand any phenotype resulting from SDF-1 administration. A recent paper by Berahovich et al. (2010) reviews the commercially available antibodies to CXCR7, and there are several small molecule inhibitors of CXCR7 available from ChemoCentryx. These will be trialled in vitro using iodinated or FITC conjugated SDF-1 and CXCR7- expressing cells in order to select the most effective blockade of CXCR7 function and then used in vivo to assess the impact of CXCR7 blockade on FAP+ cell localisation and function with and without exogenous SDF-1. Additionally, currently in development in the Fearon lab is a transgenic mouse containing an inducible Tet-off expression system under the control of the FAP regulatory elements with a TetO operator controlling the expression of Cre; this allows inducible FAP+ cell-specific expression of Cre. This will be crossed with Cxcr7(flox/-) mice (Yu et al. 2011) in order to produce conditional knockout of CXCR7 in FAP+ cells. The effect of CXCR7 blockade or knockout will be analysed by FACS and histology of tissues and blood, with particular attention paid to evidence of cell migration or apoptosis. CXCR7 blockade with small molecule inhibitors in murine cancer models have been performed and demonstrated reduced tumour volume (Burns et al. 2006), however, the studies were conducted on immunodeficient mice or using syngeneic tumours. Using the cachexia-inducing subcutaneous C26 tumour model (Zhou et al. 2010), in combination with CXCR7 knockout in FAP+ cells, we will be able to specifically observe the effect of CXCR7 function on FAP+ cells and its impact on cachexia and anaemia in allogeneic tumours. It will be investigated as to whether blockade of CXCR7 is sufficient to prevent the population of the tumour with FAP+ cells, or to prevent peripheral symptoms such as cachexia. Validation of chemokine receptor expression by FAP+ cells will take approximately six months, during which time STU 06/11 Science 7 reagents required for CXCR7 blockade will be tested and optimised in vitro and the subcutaneous C26 tumour model will be established. Following this, preliminary in vivo blockade of CXCR7 will be done and tissues analysed. The FAP-Tet-off; TetO Cre mouse is currently in development and is predicted to be available to cross to the floxed CXCR7 mouse within 6-8 months, and the mice should be ready to use within one year. This will enable characterisation of the effects of CXCR7 knockout in FAP+ cells. Alongside this project, serum will be collected from KPC mice for SDF-1 analysis by ELISA. Analysis of this data should be completed within three months, enabling the osmotic pump experiments to begin and to run in parallel with the CXCR7 project.
Initially, it was thought that just 5% of the human genome was transcribed, around one fifth of which can be accounted for by the 20,000 or so known protein-coding genes, or the messenger RNAs (1 ). However mapping and quantification of the mammalian transcriptome has shown that the number of transcripts encoded by the human genome is at least 10 times as great as the number of identified 'genes' (2, 3) that up to 70% of the mammalian genome is transcribed (4). Much of the uncharacterised transcriptors appears to be composed of long non-coding RNAs (lncRNAs), defined as RNA transcripts greater the 200nt (5), 34 of which have so far been associated with human disease (6). To begin the genome-wide search for candidate lncRNAs associated with heart failure, the Foo lab carried out RNA-seq on RNA isolated from four human control hearts and four diseased hearts. Diseased he are from male subjects, aged 40-60 years with a well-documented medical history. RNA-seq is a high throughput sequencing technique in order to obtain information about the biological system's total RNA repertoire (7). The resulting information is a summary statistic- a form of 'read count' that is linearly related to the abundance of the transcript in the sample. Figure 1 shows a diagrammatical outline of a typical RNA-seq experiment. Verify differential expression of transcripts in a larger sample of human heart tissue. Obtain complete sequence of the non-coding transcript. For the RNA-seq derived RNAs, does the transcript reside in myocytes or fibroblasts of cardiac tissue? Ensure that the transcript of interest does not yield a product of translation. What happens when the transcript is overexpressed and repressed in wild type cardiomyocytes or fibroblasts in culture? Is the Inc RNA of interest upregulated in response to stress triggers? What are the interactors of a novel Inc RNA?
Delineation of brain-derived-neurotropic factor (BDNF) neurons modulating energy balance. 19 Mar 2012
Aim 1: (a) To characterize the regulation of hypothalamic brain-derived-neurotrophic factor (BDNF) expression by serotonin and melanocortin compounds and (b) determine whether BDNF is required for serotonin and melanocortin compounds to elicit effects on energy balance. Aim 2: To characterize the effect of ventromedial nucleus of the hypothalamus (VMN) steroidogenic factor 1 (SF-1) BDNF-expressing neurons on the effect of serotonin and melanocortin compounds modulating energy balance. Aim 3: To characterise the specific effect of VMN SF-1 BDNF-expressing neurons on energy balance.
Disorders of weight regulation such as obesity and anorexia nervosa are frequently associated with neuroendocrine abnormalities. Genetic studies in patients with severe obesity have highlighted the role of the hypothalamic leptin-melanocortin pathway in energy homeostasis, reproduction, growth and thyroid hormone synthesis. We have identified 230 severely obese patients with central hypothyroidism and/or hypogonadism that cannot be explained by mutations in known genes. The aim of my proposal is to identify novel low frequency/rare genetic variants in these patients using whole exome sequencing (exon capture using the Agilent SureSelect system; sequencing using Illumina GII platform), to compare this data to data from 2000 patients with severe obesity alone and 4000 controls sequenced as part of the UK10K project. This work will be conducted in collaboration with Dr Ines Barroso at the Wellcome Trust Sanger Institute, where I will receive training in the analysis and interpretation of this data. I will investigate co-segregation of genetic variants in families, examine the impact of mutations on the functional properties of the proteins involved and conduct endocrine and metabolic studies. My long term aim is to make a significant contribution to the understanding of the mechanisms underlying the neuroendocrine consequences of obesity.
Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain 24 May 2012
Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics. IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction. The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.
The aim of this project is to define the structural basis of the mechanism of action of the Cys loop family of neurotransmitter receptors. The roles and specific chemical interactions of amino acid residues in both 5-HT3 and GABAc receptor binding sites, and in the protein subdomains that link and drive channel opening, will be characterised, using both theoretical (modelling, docking, molecular dynamics) and experimental approaches (mutagenesis, radioligand binding, functional assays, fluoresce nce measurements, structure determination). The key goals are defining (a) the molecular interactions that are critical for the binding of 5-HT or GABA and other agonists and antagonists; (b) the molecular interactions in the binding site that initiate receptor gating; (c) the conformational changes that occur in the extracellular ligand-binding site as a result of agonist binding; (d) how these changes are transduced to the pore lining M2 domain; and (e) how M2 moves to open the channel.
Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Molecular imaging of glycosylation changes in Barrett's oesophagus to detect dysplasia: endoscopic and radiological applications.' 31 Aug 2012
To determine whether glycans can be used as molecular imaging targets. We hypothesise that labelled glycan can be detected endoscopically and thereby guide biopsies to macroscopically normal areas of dysplasia within Barrett’s oesophagus as prior to more generalized application in the aerodigestive tract.An in vivo endoscopic molecular imaging study using lectin-guided biopsies in the surveillance of BE will be completed as well as adapting a bioorthogonal chemistry approach from an animal model to label the human oesophageal glycome in human organ culture as a step towards to imaging of the human glycome without the application of lectins for imaging.
Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2012 MPhil Appointments. 31 Aug 2012
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.
How to build a retina. 26 Nov 2012
Fascinated by how an organ as complex and refined as the brain is made through instructions encoded in DNA, I focus on the retina, perhaps the most experimentally tractable part of the brain (Figure 1). Three basic and interrelated questions form the core of this proposal: 1. Vertebrate species have different sized retinas. What mechanisms regulate the appropriate number of neurons generated from a population of retinal progenitor cells (RPCs) that themselves produce variable numbers of desce ndant neurons? 2. In all vertebrates, retinal cells consist of six main types and more than 50 subtypes. How are these types and subtypes generated in the correct proportions? 3. A conserved feature of retinal development is histogenesis, the relationship between cell birth, cell type, and tissue architecture. How is this achieved? Breakthroughs in time-lapse imaging, molecular biology and quantitative analysis allow us now to address these fundamental yet unsolved questions. Answer s to them should reach beyond the retina to other developmental systems, particularly the brain. We hope to resolve molecular regulatory pathways that underlie these processes and discover mechanisms that unify and coordinate proliferation, cell fate determination and tissue architecture.
Causal inference in large datasets using genetic instrumental variables: extending Mendelian randomization techniques. 31 Oct 2012
My key goal is the development of techniques for understanding the underlying causal mechanisms behind biological processes using information about genetic variants in population-based studies. In particular, I aim to find and validate causal risk factors and biological pathways responsible for cardiovascular disease (CVD). Methods development: I will develop methods for the extension of Mendelian randomization to the detailed analysis of complex causal networks between measured variables, a nd the integration of large-scale genetic data with data on exposure variables from multiple data sources. Applied analysis: This will involve the analysis of large-scale datasets on cardiovascular risk, including a case-cohort study in Europe and a case-control study in Pakistan each with more than 10,000 CVD cases. The breadth of the data facilitates detailed assessment of the assumptions on which Mendelian randomization relies. The aim is the categorization of risk factors by their causal role, including mediators in causal pathways, and the direction of causal association between different factors. Dissemination of methods: I will engage the epidemiological and wider medical community using illustrative papers, communicating the potential of the methods available to a wide audience. One aim is to develop a software package for investigators working in Mendelian randomization.