Altered contractile protein expression and increased smooth muscle cell proliferation are characteristics of many vascular and pulmonary diseases. The long-term goal of this proposal is to unravel the mechanisms regulating the expression of smooth muscle-specific expression of telokin, a small myosin binding protein, will be elucidated. The overall hypothesis to be evaluated is that binding of tissue-specific nuclear proteins to cis-acting elements in the telokin promoter, regulates telokin transcription in smooth muscle. A corollary of this hypothesis is that the differential expression of telokin in visceral and vascular smooth muscle, results from either different levels of nuclear regulatory proteins or form unique nuclear proteins in each of the smooth muscle tissues.
Four Specific Aims are proposed to address this hypothesis. Experiments will first determine if telokin expression is restricted to smooth muscle cells throughout development, and determine the temporal pattern of telokin expression relative to other smooth muscle-specific proteins. The cis-acting elements in the telokin promoter that regulate telokin expression in smooth muscle tissues will be identified in cultured cells and in transgenic mice. The factors that bind to important regulatory elements will then be identified and cloned. Once regulatory factors have been cloned, their tissue and developmental pattern of expression will be analyzed and their role in regulating the expression of telokin and other smooth muscle genes determined. These studies will help unravel the complex network of interactions that ultimately results in smooth muscle differentiation and provide reagents that can be used to design smooth muscle-specific gene delivery systems.
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