REGULATION OF MATRIX GENE EXPRESSION BY B-MYB

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The transcription factor B-Myb, a member of the myb gene family, displays a relatively ubiquitous pattern of expression. Recently the PI has demonstrated that B-myb is expressed in bovine aortic smooth muscle cells (SMCs). Vascular SMCs are responsible for synthesis of the bulk of the matrix proteins within the medial layer of major arteries and within the intima during formation of an atherosclerotic plaque. In cultured SMCs, B-myb expression was found to relate directly to the cellular proliferative state while collagen gen expression varied inversely. Importantly, B-myb down- regulated activity of the promoters of types I and V collagen and elastin genes in SMCs. Thus, the hypotheses that B-Myb represents an important regulator o collagen gene transcriptions and is, in part, responsible for the decreased pattern of collagen gene expression in rapidly proliferating SMCs will be tested in this application. The specific aims are to 1) characterize B-myb mRNA and protein expression as a function of cell density in culture and treatment with basic fibroblast growth factor (bFGF), and stage of aortic development; 2) elucidate the mechanism(s) of B-Myb-mediated down-regulation of the promoters of the alpha 2(V) and alpha 2(I) collagen chains; 3) determine the functional role of B-myb expression in formation of the vessel wall using the SM22a gene promoter in a transgenic mouse model. These studies should shed light on B-myb gene expression and the role of this transcription factor control of matrix production and formation of the normal vessel wall. These findings would have particular relevance to our understanding of diseases involving excess matrix deposition by the vascular SMC, such as atherosclerosis and restenosis, and potentially for other SMCs as well, such as uterine SMCs, which ar responsible for fibroid formation (the leading cause of hysterectomy in the United States). Lastly, information should be obtained on the possible role for B-myb as-an anti-fibrotic gene, of significant potential importance to a wide range of fibrotic diseases in the liver, lung, and other organs.