Objectif MicroRNAs are small non-coding RNAs involved in cell homeostasis and carcinogenesis. MicroRNA deregulation is associated with colorectal cancer (CRC) progression. My study proposes to identify genetic and epigenetic events leading to microRNAs deregulation and use them as targets for drug development. My research proposal will address two important questions. First it will assess the contribution of genetic and epigenetic events in controlling microRNA genes and cancer phenotype. Second it will define synthetic lethal interaction between microRNA genes aberration and kinase genes in order to define novel target for therapy.Mutations and promoter methylation of microRNA genes and microRNA processing genes will be analyzed by massive parallel sequencing in a first cohort of CRC. Mathematical and in vitro analysis will be performed to test whether a mutation is a driver or passenger one. The frequency of driver mutations and promoter methylation will be confirmed in a large case-control study encompassing 2500 CRC patients. Mutational and methylation status will be matched with clinical-pathological features in order to detect correlations with clinical outcome. In order to translate my findings into drug development, genetic aberration in microRNA genes will be reproduced in CRC cell lines. Isogenic cell lines harboring the wild type or the mutant allele will be tested for cell viability in a parallel RNAi screening using siRNA libraries targeting kinase. Protein kinases are important mediators of microRNA function. More importantly, catalytic inhibitors of kinase can be easily developed making them attractive targets for synthetic lethality screening and drug development. Champ scientifique medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesclinical medicineoncologycolorectal cancernatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicinephysiologyhomeostasisnatural sciencesbiological sciencesgeneticsepigenetics Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Appel à propositions FP7-PEOPLE-2012-CIG Voir d’autres projets de cet appel Régime de financement MC-CIG - Support for training and career development of researcher (CIG) Coordinateur INSTITUTE OF CANCER RESEARCH: THE ROYAL CANCER HOSPITAL LBG Contribution de l’UE € 9 341,39 Adresse OLD BROMPTON ROAD 123 SW7 3RP London Royaume-Uni Voir sur la carte Région London Inner London — West Kensington & Chelsea and Hammersmith & Fulham Type d’activité Higher or Secondary Education Establishments Contact administratif Angus Bell (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Participants (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire UNIVERSITY OF GLASGOW Participation terminée Royaume-Uni Contribution de l’UE € 90 658,61 Adresse UNIVERSITY AVENUE G12 8QQ Glasgow Voir sur la carte Région Scotland West Central Scotland Glasgow City Type d’activité Higher or Secondary Education Establishments Contact administratif Derek Motherwell (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée