In response to injury and in certain disease states such as atherosclerosis, normally quiescent medial smooth muscle cells migrate to the intima where they undergo some rounds of proliferation and deposit abundant quantities of matrix components, thus predominantly contributing to vessel occlusion. This Program Project is dedicated to the investigation of molecular mechanisms of regulation of the production of matrix macromolecules by arterial smooth muscle cells in culture and in transgenic mice and vascular tissue models in response to agents and conditions implicated in atherogenesis. We hypothesize that common factors or mechanisms may link the fibrogenic and proliferative capacities of the arterial smooth muscle cells, detailed knowledge of which should elucidate potentially effective means of controlling arterial disease. The first project will principally address the factors affecting B-myb expression and the mechanism by which B-myb down-regulates matrix gene expression. The second project will explore the role of adenosine and its arterial smooth muscle cell receptors in vascular function and matrix protein production. The third project will pursue the analysis of transcriptional and post-transcriptional mechanisms by which smooth muscle cell lysyl oxidase is regulated and will explore the potential function of this amine oxidase within the nucleus of these cells. The fourth project is focused on the regulation of elastin production of IGF-I, addressing the interplay of cis- and trans-acting factors influencing both elastin gene transcription and events related to G1 progression in the cell cycle. The research of these closely integrated projects will rely upon the services of the Biomodel Core which will provide cell culture models and analytical services for analysis of transgenic models. Thus, this Core and the Administrative Core will facilitate a highly interactive approach to achieve the goals set forth. The proposed studies should enhance our understanding of the mechanisms that regulate matrix production and vascular function in normal and pathological conditions.
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