Three clear objectives, with defined milestones, are at the heart of this project:
Identification of adhesion molecules implicated in initiating and perpetuating atherosclerotic lesions. An important aspect of this work will be to compare data from transgenic Apo(e) mouse used in different models (diets and/or heterotypic cardiac transplantation), to pig atherosclerosis and to results observed in human spontaneous or transplantation associated coronary artery disease. Coronary endothelial or smooth muscle cDNA libraries, in a panning technique, will be used to isolate and sequence the cDNA clones of new adhesion molecules or their ligands
Testing the role of adhesion molecules in atherosclerotic lesions (P-selectin and ICAM-1 are lead candidates) by using Apo(e) transgenic animals lacking P-selectin and/or ICAM-1 expression (double or triple knock outs). Loss of these adhesion molecule genes, in transgenic animals, will also be evaluated in heterotypic cardiac transplantation. The role of different adhesion molecules and/or platelet activating factor (PAF) will be tested in adhesion or coculture chamber assays to look at the binding and extravasation of monocytes and T Iymphocytes.
Validation of the role played by adhesion molecules in atherosclerotic lesions will be evaluated in different Apo(e) transgenic animal models (on diets and/or heterotypic cardiac transplantation) with linear or cyclic peptides. Such validation of the role played by adhesion molecules will also be performed in the porcine model of vascular reperfusion injury and restenotic injury using blocking monoclonal antibodies or peptides.
Complications following atherosclerotic plaque formation are responsible for about half of total death in the European Union. The cost of such disease to member states is rapidly increasing with the rise of wealth and standard of living. Generation of new drugs to prevent plaque initiation, perpetuation or even rupture could have a tremendous impact on public health and in promoting European Union pharmaceutical industry to the forefront of the economic and industrial competition for what would be a global market. The mechanisms allowing the initiation, progression and rupture of atherosclerotic plaques, in arteries occlusion, remains to be identified. Moreover, very little is known on transplant associated coronary artery disease which is the most serious long term complication and is a possible limitation to the long term success of cardiac transplant programmes. However, increasing evidence shows that activated vascular endothelial cells, occurring as a result of various possible insults, will upregulate and/or express adhesion molecules that will allow the rolling, adhesion and extravasation of monocytes / macrophages and a subpopulation of T lymphocytes to subintimal areas. The initiation and perpetuation of atherosclerotic lesions appear to be mediated by these vascular endothelial adhesion molecules. This study will set up a multidisciplinary network of European Union laboratories with the aim of developing new concepts of adhesion blockade to a stage where therapy might be attempted. The multidisciplinary structure of this project, its cutting edge technology, and the experience of its network in adhesion molecules and/or in atherosclerosis gives it a clear lead in reaching its objectives in the generation of new compounds to be used in drug development.