Role of miR-145 in Vascular Smooth Muscle Cell BiologyRole of

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DESCRIPTION (provided by applicant): Role of miR-145 in Vascular Smooth Muscle Cell Biology MicroRNA (miRNA) have emerged as a novel class of endogenous, small, noncoding RNAs that negatively regulate over 30% of genes in a cell via degradation or translational inhibition of their target mRNAs. Functionally, an individual miRNA is important as a transcription factor because it is able to regulate the expression of its multiple target genes. It is therefore not surprising that miRNAs are involved in the regulation of all major cellular functions such as cell differentiation, proliferation and migration. Recently, we have found that microRNA-145 (miR-145) is the most abundant miRNA in vascular smooth muscle cells (VSMCs) and its expression is significantly downregulated in VSMCs of vascular walls with neointimal lesion formation in vivo and in cultured dedifferentiated VSMCs in vitro. However, the role of miR-145 in the VSMC biology is currently unclear. It is well established that the transition of VSMCs from a differentiated phenotype to a dedifferentiated state, which is accompanied by accelerated migration and proliferation, plays a critical role in the pathogenesis of a variety of proliferative vascular diseases such as atherosclerosis and restenosis. Our long-term goals are to determine the roles of miRNAs in VSMC biology and their contribution to proliferative vascular diseases. The goal of this proposal is to determine the role of miR-145 in VSMC phenotypic modulation, proliferation, migration and vascular neointimal lesion formation, and to elucidate the molecular mechanisms involved. Our central hypothesis is that miR-145 is a critical modulator for VSMC phenotype, proliferation, migration, vascular neointimal growth and atherosclerotic lesion formation via its target genes, kruppel-like factor 5 (KLF5) and kruppel-like factor 4 (KLF4). Our hypothesis is supported by our preliminary studies. We will further test our hypothesis by the following four specific aims: Aim 1 is to determine the roles of miR-145 in VSMC phenotypic modulation, proliferation, and migration in cultured VSMCs in vitro. Aim 2 is to determine the roles of miR-145 in VSMC phenotypic modulation, proliferation, migration, and vascular neointimal growth in injured rat carotid arteries in vivo. Aim 3 is to determine the role of miR-145 in atherosclerotic lesion formation and its cellular mechanisms in Apo E knockout mice. Aim 4 is to elucidate the molecular mechanisms that are responsible for miR-145-mediated effects on VSMC phenotype, proliferation, migration and vascular neointimal and atherosclerotic lesion formation. These aims will be accomplished by utilizing the latest cellular, molecular, and whole animal approaches including transgenic and gene knockout mice. The current proposal will identify an entirely new regulator for VSMC phenotype, proliferation, migration and vascular neointimal and atherosclerotic lesion formation. These findings from this innovative research area may have extensive implications for the diagnosis and treatment of a variety of proliferative vascular diseases, such as atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. PUBLIC HEALTH RELEVANCE: MicroRNA-145 (miR-145) is the most abundant microRNA in vascular smooth muscle cells (VSMCs) and its expression is significantly downregulated in VSMCs of vascular walls with neointimal lesion formation in vivo and in cultured dedifferentiated VSMCs in vitro. However, the role of miR-145 in the VSMC biology and its potential contribution in the development of vascular disease are unclear. The goal of this project is to determine the role of miR-145 in VSMC biology and vascular neointimal lesion formation and to elucidate the molecular mechanisms involved.