Objectif Ion channel genes have long been linked to Mendelian focal epilepsies, but my recent finding of frequent mutations in DEPDC5 opens completely new perspectives. DEPDC5 is an inhibitor of the mTORC1 (mammalian target of rapamycin) signaling pathway, the master regulator of cell proliferation and growth. Mutations of this gene are found in a wide spectrum of focal epilepsy syndromes, with or without cortical malformations. I propose to examine the links between DEPDC5 and the mTORC1 pathway in cortical development and the genesis of epileptic activity. My proposal work will combine high-throughput sequencing, in vivo proteomics, biochemistry, electrophysiology, and animal behavior testing (video-EEG). Functional analyses will be made on human postoperative tissue and neuronal cultures from human iPSC and specific rodent models. These approaches will enable me to (1) ask if and how the mTORC1 signaling pathway may contribute to epileptogenesis and seizures in patients with DEPDC5 mutations, (2) attempt to explain the diversity of phenotypes, in particular the presence of cortical lesion by searching for somatic brain mutations in the gene, (3) explore neurobiology pathways and partners of DEPDC5, and (4) identify novel actors for inherited focal epilepsies.Our results will help us understand the genesis of epileptic networks, and more generally how defects in mTORC1 signaling cascade cause neurologic conditions. We anticipate genetic studies on germline and somatic mutations will have a significant clinical impact for genetic counseling and improved prognosis. The molecules and pathways that will be studied in this proposal differ completely from ion channels and receptors that have been so far associated with focal epilepsies. Thus I hope to provide a new orientation for the field, to identify novel genetic mechanisms and to provide an unbiased route to new molecular therapeutic targets. Champ scientifique natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicineneurologyepilepsymedical and health sciencesclinical medicinesurgerynatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesbiological behavioural sciencesethology Mots‑clés Epilepsy mTOR pathway next-generation sequencing genetically-modified mice models Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-CoG-2015 - ERC Consolidator Grant Appel à propositions ERC-2015-CoG Voir d’autres projets de cet appel Régime de financement ERC-COG - Consolidator Grant Institution d’accueil INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE Contribution nette de l'UE € 1 998 760,00 Adresse RUE DE TOLBIAC 101 75654 Paris France Voir sur la carte Région Ile-de-France Ile-de-France Paris Type d’activité Research Organisations Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 998 760,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE France Contribution nette de l'UE € 1 998 760,00 Adresse RUE DE TOLBIAC 101 75654 Paris Voir sur la carte Région Ile-de-France Ile-de-France Paris Type d’activité Research Organisations Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 998 760,00
