Arteriosclerosis remains the principal cause of myocardial infarction, stroke, and peripheral vascular disease in developed societies. Although the proliferation and de-differentiation of vascular smooth muscle cells (VSMC) is critical for the development of the arteriosclerotic lesion, the molecular mechanisms regulating these events are poorly understood. The long-term objectives are to define the molecular mechanisms regulating the growth and differentiation of vascular smooth muscle cells. Previously, they have identified and characterized a novel zinc-finger transcription factor named SmLIM that is highly and preferentially expressed in VSMC. Other members of this group of proteins have been shown to play essential roles in the development, growth, and differentiation of specific cell types. Thus, they hypothesize that SmLIM plays a similar role in VSMC. This proposal aims to investigate the role of SmLIM in regulating the state of VSMC differentiation and to define the molecular mechanisms regulating its preferential pattern of expression in VSMC. To assess the role of SmLIM in regulating the VSMC phenotype, they will establish stable clones overexpressing SmLIM in the sense and antisense orientations. They will then assess clonal characteristics such as growth, contractility, and expression of various markers of differentiation to determine SmLIM function in VSMC. SmLIM is highly and preferentially expressed in VSMC. Gene transcription is regulated by the interaction of specific DNA sequences (cis-acting elements) and their cognate binding proteins (trans-acting factors). Thus, they plan to identify and characterize the cis-acting elements and trans-acting factors important in regulating SmLIM expression. The proposed work will allow them to understand the importance of SmLIM in regulating VSMC growth and differentiation. Furthermore, identification of VAMC-specific cis- and trans-acting factors will be crucial to the future success of efforts to restrict the expression of foreign genes to the blood vessel wall for gene therapy of vascular disease.
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