Objective Atherosclerosis is considered to be a chronic inflammatory process. Arterial inflammation that precedes plaque development is caused by accumulation of LDL (low density lipoproteins) in the extracellular matrix of the vessels. These LDL particles are modified by a number of processes, including enzymatic degradation, aggregation and oxidation. Complement is also emerging as an important factor in this process: complement activation and formation of the terminal C5b-9 membrane attack complex were shown to occur in atherosclerotic lesions. Recently we have studied the ability of enzymatically modified LDL (E-LDL) to activate C1, the complex that triggers the classical pathway of complement. E-LDL is recognized by the C1q subunit of C1 and triggers direct C1 activation, suggesting that complement activation by E-LDL may play a crucial role in the pathogenesis of atherosclerosis. The objective of this proposal is to characterize the mechanisms involved in the recognition of E-LDL by C1q. We aim at (i) identifying the molecules recognized by C1q; (ii) characterizing the molecular mechanisms involved in this recognition; and (iii) analyzing the mechanisms underlying E-LDL-mediated C1 activation. The project is based on approaches at the molecular and structural levels, and will involve protein biochemistry methods, X-ray crystallography, surface plasmon resonance spectroscopy and functional studies. From a fundamental standpoint, the immediate benefit of this work will be to improve our knowledge of the mechanisms that allow C1q to act as a “sensor” of altered self structures. The biomedical applications of our results could have a considerable impact in the development of new therapeutic strategies against atherosclerosis, because the molecular mapping of the interaction between E-LDL and C1q could help design and synthesize molecules able to interfere with this interaction and thereby to control or prevent complement activation. Fields of science natural scienceschemical scienceselectrochemistryelectrolysisnatural sciencesearth and related environmental sciencesgeologymineralogycrystallographymedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisengineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsnatural sciencesphysical sciencesopticsspectroscopy Keywords Atherosclerosis Complement system Health sciences Immunology Low density lipoproteins 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) Topic(s) PEOPLE-2007-2-1.IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Call for proposal FP7-PEOPLE-2007-2-1-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS Address Rue michel ange 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Jean-Xavier Boucherle (Dr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data
