Objectif Autophagy is a conserved, highly regulated degradative pathway transferring cytoplasmic components in autophagosomes to lysosomes providing energy for cellular metabolism. In multicellular organisms autophagy is essential for tissue homeostasis and deficient autophagy is implicated in a broad range of diseases e.g. cancer and neurodegenerative disorders. To develop therapeutic strategies targeting autophagy a comprehensive understanding of the molecular protein machinery mediating and regulating autophagy is required.In a genome wide siRNA screen the host laboratory identified SCOC, a small Golgi protein, as a novel positive regulator of starvation-induced autophagosome formation. SCOC forms a complex with FEZ1, which also contains ULK1. FEZ1 negatively regulates autophagy and FEZ1 and the related FEZ2 associate with ULK1 and mTORC1 kinase complexes. The TOR signalling pathway is central in nutrient sensing. Starvation inactivates mTOR kinase leading to ULK kinase activation and autophagy induction. SCOC and FEZ also interact with the tumor suppressor UVRAG, a subunit of class III Beclin1-PI(3)K lipid kinase complexes essential for autophagy induction and progression. Autophagy is crucial for nervous system development and neuronal survival. Interestingly, SCOC and FEZ1 are highly expressed in neurons and required for axon elongation in C. elegans.I hypothesize that SCOC and FEZ are membrane-proximal scaffold and adapter proteins important in regulating and coordinating the three key autophagic signalling complexes, mTORC1, ULK1 and UVRAG-Beclin1-PI(3)K. I aim to understand the molecular details of this function and how they relate to vertebrate nervous system development and homeostasis. Our multidisciplinary approach (biochemistry, biophysics, cell biology, imaging and zebrafish techniques) characterizing SCOC and FEZ function may also impact development of new therapeutic strategies in targeting autophagy in disease. Champ scientifique natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologynatural sciencesmathematicspure mathematicsmathematical analysisfunctional analysismedical and health sciencesbasic medicinephysiologyhomeostasis 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-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2012-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur CANCER RESEARCH UK LBG Contribution de l’UE € 221 606,40 Adresse 2 Redman Place E20 1JQ LONDON Royaume-Uni Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Holly Elphinstone (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
