- Total grants
- Total funders
- Total recipients
- Earliest award date
- 12 Jan 2008
- Latest award date
- 17 Dec 2008
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
At the current time, approximately 25% of the genetic risk of breast cancer is explained by a combination of rare, high or moderate penetrance genes and common, low penetrance variants. Existing evidence suggests that much of the residual risk is mediated by many, possibly hundreds, of common variants that each confers a small increase in risk. The key goal of this research is to conduct a genome-wide association study to identify such breast cancer susceptibility alleles. In the first stage, 4,000 genetically enriched breast cancer cases and matched controls will be typed for 550,000 SNPs using the Illumina Infinium Duo 550k array, and genotypes will be compared with existing data on the 550k array available from the 1958 birth cohort. Associations identified in this genome-wide experiment will then be followed up in further stages involving a large, international consortium of an additional 40,000 breast cancer cases and 40,000 controls. Power calculations indicate that this design will identify most common variants that each explain at least 0.2% of the familial risk of the disease. Together, these detectable variants may explain much of the genetic variance of breast cancer.
The role of the ovary-specific cap-binding protein in regulation of translation in early development . 30 Apr 2008
In early development, during the period from the meiotic maturation of oocytes to eggs through to onset of zygotic transcription in the fertilised embryo, the principal means of gene regulation is translational control of the masked maternal mRNA. The cytoplasmic polyadenylation element binding protein (CPEB) is a critical regulator of translation in early development, in organisms ranging from clam to man. CPEB binds CPE elements in the 3' untranslated regions of specific mRNAs, and controls t heir expression at the level of translational repression in oocytes, and by cytoplasmic polyadenylation and translational activation in eggs. In Xenopus oocytes, CPEB is present in a large RNP complex with several highly conserved RNA-binding partners, including Xp54 RNA helicase, Pat1, and RAP55, and inhibits cap-dependent protein synthesis using a novel pairing of the eIF4E-binding protein 4E-T(ransporter) and eIF4E1b, a close homologue of the canonical cap-binding protein. Our aims are to: I. Investigate eIF4E1b interactions with the m7GpppG cap II. Investigate eIF4E1b interactions with 4E-T and eIF4G III Identify mRNAs regulated by eIF4E1b IV. Assess the function of eIF4E1b in translational control V. Investigate how the interaction between eIF4E1b and 4E-T change during meiotic maturation when translation is activated
The aims of this project are three-fold: to clarify how frequently ectopic lymphoid tissue (ELT) occurs within heart grafts and whether its presence correlates with development of chronic allograft vasculopathy (CAV), to examine how graft-ELT functions independently of conventional secondary lymphoid organs (SLOs), and to assess whether blocking ELT formation abrogates CAV development. Foci of ELT are frequently found in explanted failed solid organ transplants. In autoimmunity, immune respon ses originating within ELT may drive disease progression. Whether allograft-ELT responses similarly influence graft survival is, however, unknown. ELT formation will be studied in two mouse models of chronic cardiac allograft rejection. Heart allografts will be excised 50 days after transplantation and the presence of ELT correlated with the degree of CAV. To distinguish the alloimmune response in ELT from conventional SLOs, mice that lack SLOs will receive previously transplanted heart graft s and activation of na ve alloreactive T and B cells, dependent upon graft-ELT, assessed. These experiments will be extended to examine whether graft-ELT is a site for alloreactive T cell epitope spreading and alloreactive B cell somatic hypermutation. Monoclonal antibodies will be used to block key signalling pathways required for ELT formation and their effect on CAV development determined.
I recently developed, with Maneesh Sahani, a theoretical framework for time representation that naturally reproduces the classical scalar and Weber laws of timing, and is the first theory to account for the influence of certain stimulus attributes on human timing judgements (e.g. Kanai et al., 2006). First, I aim to explain a wider range of human behaviour by extending this framework. I will test its new predictions psychophysically. Next, I will study the representation of time using electrophy siology, building on anatomical work that is currently being carried out by Pai and Brody (personal communication) with the goal of identifying brain regions in the rat that are necessary for duration discrimination. I will make multi-unit extracellular recordings from the identified brain regions in behaving animals, under controlled stimulus conditions. My goal will be to find circuit-level correlates of time representation and timing mechanisms. After this, I will develop neural network model s of timing mechanism (e.g. by extending work by Karmarkar and Buonomano, 2007), based on the electrophysiological experimental data and our functional framework, and link them to human behaviour by incorporating sensory input into the network models. Thus, I plan to generate a comprehensive framework for neural time representation.
Chronic spinal cord compression (due to tumours, disc protrusions etc) is a common clinical problem but both the mechanisms of progressive loss of function and the effects of surgical decompression on cellular and sub-cellular physiology are incompletely understood. Both these issues are of high clinical importance, given the high incidence of cord compression and large numbers of decompressive surgeries conducted worldwide every year in human an animal patients. The host laboratory has deve loped a recently described model of chronic cord compression in which an expandable polymer sheet is placed over the cervical spinal cord. Histological examination has demonstrated that there are many deficits in myelin structure associated with compression and, furthermore, that decompression through atraumatic removal of the polymer sheet is associated with evidence of free-radical mediated cellular injury. This project will expand and quantify these preliminary observations by examining two a spects of the relationships between hypoxia, myelin disruption axonal dysfunction and axonal loss: firstly, that during chronic compression; and, secondly, that occurring immediately after decompression. These investigations will focus on the production of free radicals in compressed and decompressed tissue, disruption of nodal structure and its correlation with axonal destruction.
The Naked Scientists. 12 Nov 2008
We have developed an initiative at Cambridge University called the Naked Scientists, which uses several channels - radio, the Internet, podcasts and live discussions and demonstrations - to reach audiences of more than a million people per week, from a diverse range of ages and backgrounds. At the heart of our output is a weekly radio programme and podcast which aims to make science fun, interesting and interactive through the use of experiments, phone-ins and interviews with leading scientists. Our shows are syndicated on BBC local radio stations across the east of England and this enables us to access traditionally "hard to reach" audiences including some of the 30% of the population who listen only to local radio and are therefore unlikely to be exposed (normally) to educational science radio programming. This audience has increased by over 100% on some of the broadcasting radio stations. Meanwhile our podcast listener figures have increased by 30% per year, and our website, where all of our material is archived in text and audio formats, receives over 140 million hits per year, growing at 100% annually. Now we wish to consolidate this initial success and to capitalise upon the momentum that we've built up. Therefore, in addition to sustaining our present programme of activities, we also plan to strengthen our science news coverage, increase accessibility and usability of our existing web content, explore the potential of "Second Life" as a platform for public engagement and train new recruits as a way to share good practice and diversify our content. Most critically we wish to secure the position of Dr Chris Smith, who spearheads the Naked Scientists, by facilitating the creation of a post at Cambridge University dedicated to public engagement with science.
Kinetoplastid Bioinformatics: Expansion of GeneDB to Support and Enable Post-Genomic Research. 16 Sep 2008
The emergence of genome sequences has revolutionised the molecular and cell biology of protozoan pathogens and has led to an optimism that progress towards developing treatments for these neglected diseases is being accelerated. The aim of this proposal is to expand the protozoan genome database resource, GeneDB, to facilitate questioning of both current and emerging genomes and large functional genomic datasets. The key objectives are to improve annotation of current and emerging genomes, to in tegrate functional genomics datasets, to develop complex querying tools and to facilitate greater integration into the research community. The expansion of GeneDB will be undertaken using the current expertise in annotation and also by collaboration with other database resources to share expertise. In particular, tools for large dataset querying will be developed in collaboration with the ApiDB protozoan genome resource using their expertise. This collaboration will also bring about the ability to query large numbers of protozoan genomes from both resources. The aim of improved communication with the research community will result from interactive curation, greater outreach and the development of a training website. The outcome will be a resource that enables and accelerates research in labs around the world.
This application seeks support for a vital and fully integrated biomedical component for a major temporary exhibition exploring the human body at the University of Cambridge Museum of Archaeology & Anthropology (Feb 2009 - Nov 2010). The activity is part of a Leverhulme-funded interdisciplinary project based at the University of Cambridge, 'Changing Beliefs of the Human Body', that involves research groups in archaeology, classics, history, social anthropology and the Museum. The exhibition draws further insights from the history of science, biomedical research and artistic practice. The AIM OF THE PROJECT is to challenge common assumptions about the human body and to stimulate diverse audiences to explore ways that bodies are constructed, known, and contested in different time periods, across cultures, and through different disciplinary perspectives. The exhibition and associated activities will provide a forum for reflection and debate around pressing social, cultural and ethical issues to do with the human body, including well-being, race, gender, disability, and disease. Support from Wellcome will highlight and extend the biomedical components of the project and enhance public engagement with the themes of the exhibition. Three multi-sensory exhibits will stimulate interest in biomedical research and challenge visitors to learn about their own bodies. Loans from two National Museums will supplement the rich and diverse collections within the University. The provision of educational resources, a series of workshops and activities for families and community groups, and a catalogue will reach new audiences and encourage new ways of thinking about the human body.
The role of DNA methylation in heart failure 29 Aug 2008
To investigate if hypertrophic stimuli alters Dnmt3b expression, in vitro and in vivo. To investigate in vitro, the role of altered DNA methylation on cardiac myocy1e and fibroblast survival, cell cycle, proliferation and senescence. To investigate in vivo, the role of altered DNA methylation on cardiac hypertrophy, dilatation and angiogenesis.
Proteins VP1/2 and VP16 of herpes simplex virus type 1 (HSV-1) are essential components of the layer of protein called the tegument that lies between the virion capsid and the envelope. The aim of the project is to investigate the dynamics and compartmentalization of VP1/2 and VP16 over time in infected cells, and their interaction with each other, the virion capsid and the envelope.
MARCH-VII, a regulator of transcriptional activity and immune cell activation? The aims of my project are: (i) To determine the role of MARCH7 in the ubiquitylation and transcriptional activity of NFAT. (ii) To determine the role of MARCH7 in T-cell activation and immune regulation in vivo.
PhD Training Programme for Clinicians at the University of Cambridge: 'Neural and molecular mechanisms involved in human obesity'. 15 Jul 2008
Body mass is highly heritable and a number of genes have been identified, in which mutations lead to severe early onset obesity. The aim of my research is to investigate the molecular mechanisms involved in mediating the effects of the adipocyte derived hormone leptin on fertility through the study of naturally occurring mutations in the leptin receptor. I will also investigate the functional effects of a new obesity candidate gene, neuronal growth regular 1. These studies will provide a sound training in biochemistry and molecular biology and provide the basis for exploring the biology of novel candidates emerging from hypothesis-free approaches.
PhD Training Programme for Clinicians at the University of Cambridge: 'Generation of patient specific stem cells towards cell based therapy of inherited metabolic diseases of the liver'. 15 Jul 2008
To evaluate the potential of patient specific induced pluripotent stem cell (iPSC) derived hepatocytes to generate cells for cell transplant therapy in treating inherited metabolic diseases of the liver, a new chimeric mouse - human diseased liver model will be created. The first step will involve taking hepatocyte / skin fibroblast cells from Alpha 1 Antitrypsin deficient patients and reprogramming them in vitro to iPSCs. These cells will then be differentiated to hepatic progenitors and used to repopulate the liver of the FAH-/- mouse to produce a novel chimeric mouse - human liver model. The same patient specific iPSC derived hepatocytes will be genetically corrected and engrafted into the mouse model to try and achieve functional correction of the disease phenotype. By this we aim to 1) produce a new human hepatocyte cell line for Alpha 1 Antitrypsin deficiency 2) produce a new chimeric mouse - human liver 3) produce a new patient specific corrected human hepatocyte cell line from (1) 4) show proof of principle that engrafting the corrected cell line could be a therapeutic strategy towards treatment of A1ATD and other inherited metabolic disorders of the liver.
1. Develop and sustain a consortium functioning as a strong network by: i. Exchange of staff ii. Developing collaborative research projects iii. Regular communication between consortium members iv. Adjunct appointments of senior research scientists v. Joint academic programmes attended by trainees from THRiVE vi. Joint annual meetings vii. Joint supervision of PhD students 2. Empower institutions to build a critical mass of well trained research scientists capable of winning competitive national and international grants i. Mount modular short courses. These will contribute towards PhD and Masters training. ii. Enhance quality of masters training at KCMC (with emphasis on epidemiology, biostatistics and clinical trials), Gulu University and National University of Rwanda iii. Establish, and model, high-quality systems for selection, supervision and mentorship of fellowships/internships: ? Undergraduate internships ? Masters fellowships ? PhD training ? Post-doctoral fellowships 3. Augment the development of a conducive institutional environment i. Improve electronic communication, maintain website and facilitate high-speed internet access ii. Ensure availability of basic and advanced laboratory facilities iii. Identify/support key senior positions for supporting research training and mentoring 4. Support systems for improved governance/management of research activities i. Strengthen research administration and resource mobilization at participating institutions ii. Establish staff development programmes
Do you know what's good for you? How mathematics and statistics are used to make decisions about our health. 15 Dec 2008
Through a series of articles, interviews, podcast and online forums as part of Plus online magazine (http://plus.maths.org), this project aims to address key issues facing health policy makers and biomedical researchers, and highight the role of mathematics and statistics in this area. Aimed at the general public, but with a special focus on schools, the project will inform and stimulate debate about ethical and social questions surrounding the use of statistics in biomedicine, as well as highlight the overlaps between mathematics and biomedicine, stressing the interdisciplinary nature of the biomedical sciences.
We have been studying genetic susceptibility to clinical visceral leishmaniasis (VL) and to asymptomatic infection in skin-test positive (DTH+) individuals in the three major foci of disease in India, Brazil and Sudan. We have now accumulated DNA samples from a total of 1175 clinical VL cases in multicase families or trios/sibships from India, 526 clinical VL cases and 1160 DTH+/900 DTH- individuals from Brazil, and 235 clinical VL cases from Sudan. From these we can extract >1000 unrelated cases of clinical VL from India and match these with 1000 separately ascertained unrelated controls. Our aim is to use DNA from these unrelated cases and population controls to undertake a GWAS for India, with the full set of cases in families being used to validate regions of association using family-based allelic association tests. For Brazil, a family-based GWAS in which clinical VL will be analyzed as a qualitative trait and DTH as a quantitative trait is proposed. SNPs in positive regions will also be genotyped in cases in families to determine whether any are strongly associated with clinical VL in Sudan. Genotype data will be made available for replication studies in other geographical regions. SNP-chip data for controls will form a resource for future analysis of other complex diseases in India and Brazil.