The onset of atherosclerosis is marked by the migration of medial smooth muscle cells into the intima where these cells proliferate and produce abundant, extracellular fibers of collagen and elastin. The resulting accumulation of matrix, coupled with its ability to bind extracellular lipid, is a major source of the increasing mass of the atherosclerotic lesion. The overall goal of this project is to determine the mechanisms and regulation of arterial matrix accumulation and degradation with particular regard to the influence of atherogenic factors of both environmental and cellular origin, thus contributing knowledge essential to the eventual control of this major human disease. Toward these ends, we will employ aortic smooth muscle cell cultures which have been developed by our program as models of the normal and diseased arterial wall. These culture systems, derived from neonatal rat and rabbit aorta, respectively, exhibit structural features, matrices and metabolic responses which emulate those of the arterial wall. Thus, the opportunity is provided to control the extent of perturbant or injury exposure and to characterize intra- and extracellular regulatory responses relatively free of the analytical complexities of arterial tissue. The staff of this project includes both senior and junior faculty and supporting staff members, constituting a team of investigators with considerable expertise in the theoretical and experimental aspects of the biochemistry, molecular and cell biology, and enzymology of the extracellular matrix. The areas of expertise of the individual project leaders complement each other well, and their research efforts will be highly integrated to provide in depth analyses of the biosynthetic and degradative responses of the cell culture models to atherogenic injuries and perturbations. Project 27 is concerned with the development of cell culture models of proteolytic and lipid-induced arterial injury and with the definition of levels of regulation of collagen, elastin and lipoprotein in these models. Project 34 will investigate the regulation of specific genetic types of collagen assessing for transcriptional control mechanisms including regulatory elements and factors mediating expression, as these are influenced by atherogenic stimuli. Project 28 will be concerned with the regulation and biosynthetic processing of lysyl oxidase in these culture systems. Lysyl oxidase catalytically initiates crosslinking of elastin and collagen into insoluble fibers and thus can control the development of fibrotic lesions. Project 36 focuses on mechanisms whereby insulin-like growth factor-I differentially regulates smooth muscle cell elastogenesis as a function of age, hormone concentration, and cell type. These projects are supported by two core units providing cell cultures, molecular and immunological probes, microscopy and administrative support essential to this project.
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