This is a revised application which proposes to study the transcriptional regulation of smooth muscle myosin heavy chain (SM MHC) gene expression. It is expected that through an understanding of the control of transcription of the SM MHC gene which is required in part for the differentiated function of the smooth muscle cell we will learn more about the molecular mechanisms that control the differentiation and/or maturation of smooth muscle cells. Alterations in the differentiated state of smooth muscle cells is thought to play a key role in the development and/or progression of post-angioplasty restenosis and/or atherosclerosis. There are three specific aims as follows:
Aim 1 of this proposal will be to identify cellular and molecular mechanisms that regulate cell-type specific expression of the SM MHC gene in vascular SMC in transgenic mice.
Aim 2 will be to identify trans acting factors that interact with and regulate the activity of cis elements shown to be important in the SMC-specific regulation of the SM MHC gene identified in aim 1 with a particular emphasis on factors that bind to novel cis regulatory elements of the SM MHC gene or with SM MHC cis elements such as the CArGs that have been shown to be important in the regulation of multiple SMC differentiation genes.
Aim 3 will be to determine mechanisms responsible for altered expression of SM MHC in SMC within intimal lesions from experimental animal models of vascular injury/post-angioplasty restenosis as well as in human atherosclerotic lesions. The proposed studies represent an extension of the Principal Investigator's ongoing work and will contribute to an understanding of the mechanisms that alter the control of SMC differentiation in atherogenesis and may lead to the identification of possible new interventional therapies. In addition these studies are likely to identify DNA regulatory sequences that confer SMC specific expression that could be used for construction of vectors for SMC specific gene knockouts and/or targeting gene therapies to the vasculature.
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