My clinical training in cardiovascular disease has emphasized the numerous recent advances in the understanding and treatment of coronary artery disease, yet has raised more questions about the fundamental molecular mechanisms responsible for atherosclerosis and post-angioplasty restenosis. Localizing therapy to the sites of disease, delivering potent doses of effective therapy and achieving appropriate durations of therapy remain obstacles in the current management of cardiovascular disease. The stable genetic expression of factors capable of intervening in the molecular pathways leading from vascular injury to clinical morbidity and mortality may lead both to a better understanding of the disease processes and to effective therapies that overcome current limitations. This research proposal describes the investigation of platelet-derived growth factor (PDGF) mediation of restenosis in an iliac artery model using an adenovirus (Ad)-mediated gene transfer system. Genes for a secreted form -of the PDGF receptor and for hirudin, a potent thrombin inhibitor, will be engineered for expression and introduction into the rabbit iliac artery wall. The introduction of a gene into the local vascular milieu capable of intervening in PDGF-mediated neointimal proliferation could serve as a new generalizable strategy to study and intervene in local cardiovascular pathology. Animal model systems of atherosclerosis and restenosis will be used as targets for mediated gene transfer. Both direct in vivo transduction of endothelial cells with Ad recombinants and in vitro transduction of autologous. endothelial cells with Ad constructs followed by reimplantation into the vascular wall will be utilized for introducing genes into rabbit iliac artery segments. Genes for the secreted PDGF receptor and hirudin will be introduced into the vascular wall to examine their effects on smooth muscle cell proliferation, migration, matrix secretion, thrombosis and chemotaxis utilizing electron microscopy, light microscopy and quantitative histopathological analyses.
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