Objetivo The regulated secretion of chemical signals in the brain occurs principally from two organelles, synaptic vesicles and dense core vesicles (DCVs). Synaptic vesicle secretion accounts for the well characterized local, fast signalling in synapses. DCVs contain a diverse collection of cargo, including many neuropeptides that trigger a multitude of modulatory effects with quite robust impact, for instance on memory, mood, pain, appetite or social behavior. Disregulation of neuropeptide secretion is firmly associated with many diseases such as cognitive and mood disorders, obesity and diabetes. In addition, many other signals depend on DCVs, for instance trophic factors and proteolytic enzymes, but also signals that typically do not diffuse like guidance cues and pre-assembled active zones. Hence, it is beyond doubt that DCV signalling is a central factor in brain communication. However, many fundamental questions remain open on DCV trafficking and secretion. Therefore, the aim of this proposal is to characterize the molecular principles that account for DCV delivery at release sites and their secretion. I will address 4 fundamental questions: What are the molecular factors that drive DCV fusion in mammalian CNS neurons? How does Ca2+ trigger DCV fusion? What are the requirements of DCV release sites and where do they occur? Can DCV fusion be targeted to synthetic release sites in vivo? I will exploit >30 mutant mouse lines and new cell biological and photonic approaches that allow for the first time a quantitative assessment of DCV-trafficking and fusion of many cargo types, in living neurons with a single vesicle resolution. Preliminary data suggest that DCV secretion is quite different from synaptic vesicle and chromaffin granule secretion. Together, these studies will produce the first systematic evaluation of the molecular identity of the core machinery that drives DCV fusion in neurons, the Ca2+-affinity of DCV fusion and the characteristics of DCV release sites. Ámbito científico medical and health sciencesclinical medicineendocrinologydiabetesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesmedical and health scienceshealth sciencesnutritionobesity Programa(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) ERC-AG-LS5 - ERC Advanced Grant - Neurosciences and neural disorders Convocatoria de propuestas ERC-2012-ADG_20120314 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-AG - ERC Advanced Grant Institución de acogida STICHTING AMSTERDAM UMC Aportación de la UE € 1 806 005,05 Dirección DE BOELELAAN 1117 1081 HV Amsterdam Países Bajos Ver en el mapa Región West-Nederland Noord-Holland Groot-Amsterdam Tipo de actividad Research Organisations Contacto administrativo Yvonne Koppelman (Mrs.) Investigador principal Matthijs Verhage (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo STICHTING AMSTERDAM UMC Países Bajos Aportación de la UE € 1 806 005,05 Dirección DE BOELELAAN 1117 1081 HV Amsterdam Ver en el mapa Región West-Nederland Noord-Holland Groot-Amsterdam Tipo de actividad Research Organisations Contacto administrativo Yvonne Koppelman (Mrs.) Investigador principal Matthijs Verhage (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos STICHTING VU Países Bajos Aportación de la UE € 633 309,95 Dirección DE BOELELAAN 1105 1081 HV Amsterdam Ver en el mapa Región West-Nederland Noord-Holland Groot-Amsterdam Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Els Borghols (Ms.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos
