Molecular Medicine Approaches to the Treatment of Vascular Disease

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DESCRIPTION (provided by applicant): We plan to develop a novel molecular medicine approach for the treatment of coronary stenosis. Percutaneous transluminal coronary angioplasty has become the prevailing technique for coronary revascularization. There are over 1.5 million procedures every year. Despite technical advances in the field of interventional cardiology, of which coronary stenting has been the most significant, restenosis remains a problem diminishing long-term efficacy. Restenosis after interventional coronary angioplasty or metal stent implantation are both due to proliferation of vascular smooth muscle cells. Intracellular calcium concentration is known to control gene expression in non- proliferating vascular smooth muscle cells. It is therefore, not surprising that smooth muscle cell proliferation has been associated with changes in calcium modulating proteins. We have recently shown that a key intracellular calcium modulating protein, i.e., SERCA2a, is reduced during vascular stenosis. We hypothesize that we can regulate vascular smooth muscle cell proliferation in a therapeutic setting through regulation of SERCA2a expression levels. Specific Aim 1: Hypothesis: SERCA2a can be used therapeutically to reduce the extent of vessel stenosis. Approach: We will over-express SERCA2a in vivo using an adenoviral vector. The following parameters will serve as quantitative end-points: a) Morphological characteristics of carotid arteries, b) Inflammatory cell infiltration, c) Phenotype of vascular smooth muscle cells, d) Extent of apoptosis within the vessel wall, e) Changes in cell cycle proteins within the vessel wall.