Objectif The high energy demand of the brain predisposes it to a variety of diseases if energy supplies are interrupted. Neurons are particularly intolerant of inadequate energy supply and die or degenerate in either an acutely or chronically disturbed metabolic environment.Although neurodegenerative diseases are classically not considered to be caused by disturbed metabolism, bioenergetic defects are emerging as important pathophysiological mechanisms. Several glucose-metabolizing enzymes are involved in regulating cell survival or cell death in neurons and in other cell types, including the mitochondrial glucose-phosphorylating enzyme hexokinase II (HKII). A HKII-centered multiprotein complex, consisting of phosphoprotein enriched in astrocytes (PEA15) and possibly other proteins, has been demonstrated to function as a molecular switch regulating neuronal survival depending on the metabolic state. However, the molecular mechanism by which these protein:protein interactions are regulated remains elusive.The goal of AINIGMA and of the research proposed here is to unravel the intricate connection of glucose metabolism and the regulation of cell death pathways for neuronal viability or neuronal degeneration. By combining protein interaction studies in live induced pluripotent stem (iPS) cell-derived human neurons using novel biophysical tools such as fluorescence lifetime imaging microscopy (FLIM-FRET) and high throughput live cell RNA interference (RNAi) screens, the regulation of these protein interactions will be investigated. Finally, the impact of these interactions on neuronal survival under metabolic stress as well as the metabolic consequences of these protein interactions will be investigated.Therefore, AINIGMA will not only provide better insight into physiological and pathophysiological brain function but also form the basis for developing novel treatment approaches for acute and chronic neurodegenerative diseases. Champ scientifique natural sciencesphysical sciencesopticsmicroscopyfluorescence lifetime imagingnatural sciencesbiological sciencesgeneticsRNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes 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-2013-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Appel à propositions FP7-PEOPLE-2013-IOF Voir d’autres projets de cet appel Régime de financement MC-IOF - International Outgoing Fellowships (IOF) Coordinateur CHARITE - UNIVERSITAETSMEDIZIN BERLIN Contribution de l’UE € 161 517,00 Adresse Chariteplatz 1 10117 Berlin Allemagne Voir sur la carte Région Berlin Berlin Berlin Type d’activité Higher or Secondary Education Establishments Contact administratif Eveline Fräßdorf (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
