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COMPLEMENT AND ATHEROSCLEROSIS: MOLECULAR MECHANISM OF C1 ACTIVATION BY ENZYMATICALLY MODIFIED LOW-DENSITY LIPOPROTEINS

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.

Field of science

  • /natural sciences/chemical sciences/analytical chemistry/spectroscopy
  • /natural sciences/earth and related environmental sciences/geology/mineralogy/crystallography
  • /natural sciences/chemical sciences/electrochemistry/electrolysis
  • /natural sciences/biological sciences/biochemistry
  • /natural sciences/physical sciences/theoretical physics/particles
  • /medical and health sciences/clinical medicine/cardiology/cardiovascular diseases/arteriosclerosis

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
Activity type
Research Organisations
EU contribution
€ 171 600,91
Administrative Contact
Jean-Xavier Boucherle (Dr.)