Objectif Cardiovascular disease including coronary heart disease remains the leading cause of death worldwide. Atherosclerosis as the underlying pathology is a lipid-driven inflammatory disease of arteries giving rise to vulnerable lesions prone to rupture and thrombotic occlusion. Lesions develop at predilection sites with disturbed flow, where endothelial damage promotes intimal retention of lipoproteins and inflammatory leukocyte recruitment. Past research has largely focused on atherogenic factors and their inhibition but not on boosting a counterbalance by protective mechanisms. We have recently found that the CXCL12/CXCR4 chemokine-receptor axis protects against atherosclerosis by controlling neutrophil homeostasis and facilitating endothelial regeneration in mice. This is supported by genome-wide association studies, identifying genetic variants near CXCL12 associated with the risk of coronary heart disease. The protective regulation of endothelial repair by microRNAs also involves CXCL12/CXCR4. However, the causal and cell-specific impact of this axis remains unclear.To balance the ongoing expansion of genetic risk variants, PROVASC aims to discover/elucidate novel mechanisms for protective cell homeostasis and regeneration counteracting atherosclerosis in depth. To this end, we will dissect cell-specific effects of the CXCR4-CXCL12 axis using an array of mouse lines for conditional deletion and bone marrow chimeras to compare resident versus hemato-poietic cell compartments. We will validate a role of coding and non-coding genetic risk variants affecting CXCL12/CXCR4 in different cell types and humanized mouse models. By identifying relevant microRNAs targeting CXCL12/CXCR4, we will unravel a regulation of this axis by cell type-specific microRNAs. Given the ubiquitous relevance of CXCL12/CXCR4, we expect that the impact of such new mechanisms will extend to other chronic inflammatory diseases, allowing for tailored strategies of tissue protection and regeneration. Champ scientifique medical and health scienceshealth sciencesinflammatory diseasesmedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsmedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicinephysiologyhomeostasis Mots‑clés Atherosclerosis Chemokines microRNAs Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-ADG-2015 - ERC Advanced Grant Appel à propositions ERC-2015-AdG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Contribution nette de l'UE € 2 498 250,00 Adresse GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Allemagne Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments 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 € 2 498 250,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Allemagne Contribution nette de l'UE € 2 498 250,00 Adresse GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments 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 € 2 498 250,00
