Objetivo Type 2 diabetes has become one of the major causes of cardiovascular risk factor-induced mortality in recent years. The severe endothelial dysfunction associated with diabetes leads to both macrovascular and microvascular disorders culminating in atherosclerosis and foot ulcers. The specific molecular mechanisms underlying this impaired neovascularization are incompletely understood. One of the main hypothesis is an altered function of progenitor cells derived from the bone marrow in diabetes, associated with a decreased number and a dysfunction of proangiogenic mononuclear/endothelial progenitor cells (EPC). We propose that the easily obtained EPC from patients reflect the more general endothelial dysfunction of the adult vasculature. Previous work from our groups has shown beneficial effects of shear stress and KLF2 (Krüppel-like factor 2) on endothelial function and normalization of MAPK networks as well as the specific role of phosphatases like PTP1B in diabetes. The aim of our project will focus on studying activation pathways involving deregulated phosphorylation cascades. Especially the infrequently studied phosphatases known to take part in diabetic pathology will be monitored in EPC isolated from diabetic and healthy subjects. Next, altered MAPKinase and phosphates relays will be studied in in vitro culture modulated by small molecule inhibitors or lentiviral genetic modulation. Specifically, the beneficial role of shear stress and its linked transcription factor KLF2 on EPC function will be assessed. Finally, we will evaluate the therapeutic capacity of identified inhibitors of specific kinases and phosphatases as well as KLF2 after a genetic or physiological (shear stress) overexpression to normalize EPC/endothelial function in a mouse model of revascularization after hindlimb ischemia. This study will thus contribute to the development of pharmaceutical targets and tools necessary for preventing clinical cardiovascular complications of diabetes. Ámbito científico social sciencessociologydemographymortalitymedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineendocrinologydiabetesmedical and health sciencesbasic medicinepathology Programa(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) Tema(s) FP7-PEOPLE-2009-IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Convocatoria de propuestas FP7-PEOPLE-2009-IEF Consulte otros proyectos de esta convocatoria Régimen de financiación MC-IEF - Intra-European Fellowships (IEF) Coordinador STICHTING VU Aportación de la UE € 161 748,80 Dirección DE BOELELAAN 1105 1081 HV Amsterdam Países Bajos Ver en el mapa Región West-Nederland Noord-Holland Groot-Amsterdam Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Anton Horrevoets (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Participantes (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo VERENIGING VOOR CHRISTELIJK HOGER ONDERWIJS WETENSCHAPPELIJK ONDERZOEK EN PATIENTENZORG Países Bajos Aportación de la UE Sin datos 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 Anton Horrevoets (Prof.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos
