application) Abnormal proliferation and phenotypic change of smooth muscle cells (SMC) have been associated with pathogenesis of congenital and acquired human vascular disease. However, little is understood about the molecular mechanisms that control SMC lineage determination, proliferation and differentiation during cardiovascular development. To address these questions, the investigators chose to characterize the regulation of SM22, a gene known to be a marker for adult smooth muscle, in the mouse. During embryogenesis, this gene is first expressed in all three muscle lineages, and then becomes restricted to all different types of SMCs. Surprisingly, the SM22 promoter is active only in a subset of arterial SMCs, not visceral, nor coronary, nor vena cava SMCs. Site directed mutagenesis of the SM22 promoter reveals that the proximal CArG box is required for its temporospatial expression in transgenic mice, suggesting that SRF (serum Responsive Factor), the CArG box binding protein, may play an important role in SM22 gene regulation. The overall goal of this proposal is to define the molecular mechanisms that discern the differential expression of the SM22 promoter in different subtypes of SMCs. The project will have two major aims, 1) to define the critical sequences in the proximal CArG box that required for specific activation of the promoter in arterial SMCs. 2) to define the cis-acting elements that confer specific expression of SM22 in SMC subtypes such as visceral and vena cava SMCs. These studies represent an important aspect of current vascular research in understanding the molecular mechanisms that control SMC proliferation, differentiation and lineage determination during cardiovascular development. Elucidation of the molecular mechanisms governing SMC differentiation and determination will open up a new frontier to develop molecular gene therapies for both congenital and acquired cardiovascular diseases.
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