Therapeutic modulation of the thrombogenicity of atherosclerotic plaque

Coronary artery disease and the subsequent myocardial infarct is the primary cause of death in the western world. It is induced by an acute cessatio of the blood flow due to the formation of an occluded thrombus in or nearby an unstable atherosclerotic lesion. Whether or not thrombotic complications will ensure plaque rupture is strongly dependent on the presence of procoagulant molecules within the plaque. Interference with their activity and expression thus represents a promising approach to influence the initiation and progression of the disease. The general goal of the project is 1) to block the activity of procoagulant proteins by delivering specific inhibitors and 2) to modulate the acitivty of transcription factors regulating the expression of these proteins. Modulation will be achieved by atherosclerotic plaque-directed adenoviral and lentiviral transfer of the transgene. The viral constructs will be delivered to an advanced in vivo model of atherosclerosis and their effect will be analysed in the presence and in the absence of therapeutic low molecular substances. Furthermore, using a bone marrow transplantation model we will analyse, whether genetically manipulated bone marrow cells can be used as a therapeutic approach. We anticipate that the results will lead to new therapeutic modalities for reducing the thrombogenicity of atherosclerotic plaques, and thus preventing a myocardial infarct.