COLLAGEN GENE EXPRESSION AND ATHEROSCLEROSIS

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DESCRIPTION (provided by applicant): This Program Project retains as its theme the investigation of interacting mechanisms that regulate vascular smooth muscle cell (VSMC) proliferation and extracellular matrix production. These features are central to the development of atherosclerotic lesions. Dr. Gail Sonenshein (Project 1) will extend her findings on the roles of the myb family and NFkB in the coordinated regulation of collagen and elastin gene expression and VSMC proliferation. The mechanism of repression of matrix gene transcription by B-Myb and the roles of phosphorylation and protein interactions will be investigated. Dr. Katya Ravid (Project 2) will investigate the regulation of expression of the A2bAR gene and the role of B-Myb in proliferation-induced upregulation of this gene. She will also identify the role of this receptor in vascular function, focusing on VSMC proliferation, matrix production and vascular tone. Dr. Herbert Kagan (Project 3), will be concerned with the interactions recently found in his laboratory between lysyl oxidase (LO), the extrecellular connective tissue crosslinking enzyme, and surface membrane integrins and nuclei of VSMC. The receptors and mechanisms involved in the induction by LO of VSMC chemotaxis, suppression of cell proliferation and stimulation of collagen production will be investigated. Dr. Barbara Smith (Project 4), a new Project Leader in this Program Project, will extend her transcription. She has recently identified a transcription co-regulator (CIITA) that is induced during inflammation and acts to decrease collagen transcription. She will also investigate the role of statins in collagen gene transcription. She will also investigate the role of statins in collagen gene transcription. Overall, the research of this Program Project will be conducted with VSMCs in vitro and with transgenic mouse models of vascular injury. The program is supported by an Administrative Core and a BioModel Core. The BioModel Core, directed by Dr. Barbara Schreiber, provides a variety of services to support these projects. Of particular note, Dr. Schreiber has introduced a mouse femoral artery injury model with generates restenotic and atherosclerotic-like lesions. Each project will avail itself of this model to test hypotheses in vivo.