Obiettivo Atherosclerosis is characterized by chronic inflammation of the arterial wall. Mononuclear cell recruitment is driven by chemokines that can be deposited e.g. by activated platelets on inflamed endothelium. Chemokines require oligomerization and immobilization for efficient function, and recent evidence supports the notion that heterodimer formation between chemokines constitutes a new regulatory principle amplifying specific chemokine activities while suppressing others. Although crucial to inflammatory disease, this has been difficult to prove in vivo, primarily as chemokine heterodimers exist in equilibrium with their homodimer counterparts. We introduce the paradigm that heteromerization of chemokines provides the combinatorial diversity for functional plasticity and fine-tuning, coining this interactome. Given the relevance of chemokine heteromers in vivo, we aim to exploit this in an anti-inflammatory approach to selectively target vascular disease. In a multidisciplinary project, we plan to generate covalently-linked heterodimers to establish their biological significance. Obligate heterodimers of CC and CXC chemokines will be designed using computer-assisted modeling, chemically synthesized and cross-linked, structurally assessed using NMR spectroscopy and crystallography, and subjected to functional characterization in vitro and reconstitution in vivo. Conversely, we will develop cyclic beta-sheet-based peptides binding chemokines to specifically disrupt heteromers and we will generate mice with conditional deletion or knock-in of chemokine mutants with defects in heteromerization or proteoglycan binding to be analyzed in models of atherosclerosis. Peptides will be used for molecular imaging and chemokine heteromers will be quantified in cardiovascular patients. Campo scientifico medical and health sciencesclinical medicineangiologyvascular diseasesmedical and health scienceshealth sciencesinflammatory diseasesnatural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy Programma(i) 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) Argomento(i) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Invito a presentare proposte ERC-2009-AdG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-AG - ERC Advanced Grant Istituzione ospitante LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Contributo UE € 2 500 000,00 Indirizzo GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Germania Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Higher or Secondary Education Establishments Ricercatore principale Christian Weber (Prof.) Contatto amministrativo Danny Duhme (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (2) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Germania Contributo UE € 2 500 000,00 Indirizzo GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Mostra sulla mappa Regione Bayern Oberbayern München, Kreisfreie Stadt Tipo di attività Higher or Secondary Education Establishments Ricercatore principale Christian Weber (Prof.) Contatto amministrativo Danny Duhme (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato UNIVERSITAETSKLINIKUM AACHEN Partecipazione conclusa Germania Contributo UE Nessun dato Indirizzo Pauwelsstrasse 30 52074 Aachen Mostra sulla mappa Regione Nordrhein-Westfalen Köln Städteregion Aachen Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Volker Legewie (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato