REGULATION OF MATRIX GENE EXPRESSION BY B-MYB

转录因子B-Myb是MYB基因家族的成员， 显示了一种相对普遍的表达模式。最近 PI已证明B-MYB在牛主动脉中有表达 平滑肌细胞(SMC)。血管SMC负责 内侧膜内基质蛋白的合成 在血管形成过程中的主要动脉层和内膜内 动脉粥样硬化斑块。在培养的SMC中，B-MYB的表达 发现与细胞增殖状态直接相关，而 胶原蛋白的表达则相反。重要的是，B-MYB下降- I型和V型胶原启动子的调节活性和 SMC中的弹性蛋白基因。因此，B-Myb代表的假设 胶原蛋白基因转录的重要调节因子，在 部分，负责胶原基因的减少模式 在快速增殖的SMC中的表达将在此进行测试 申请。其具体目的是：1)鉴定B-MYB基因 和蛋白质表达作为培养和培养中细胞密度的函数 碱性成纤维细胞生长因子(BFGF)治疗，分期 2)阐明B-Myb介导的血管生成机制(S) α2(V)和α2(I)启动子的下调 胶原链；3)确定B-myb的功能作用 SM22a基因在管壁形成中的表达 转基因小鼠模型中的启动子。这些研究应该摆脱 B-myb基因的表达及其转录的作用 基质产生的因素控制和正态的形成 血管壁。这些发现将对我们的 对涉及过度基质沉积的疾病的认识 血管SMC，如动脉粥样硬化和再狭窄，以及 可能也适用于其他SMC，如子宫SMC，它们是 肌瘤形成的主要原因 美国的子宫切除术)。最后，信息应该是 关于B-myb作为一种抗纤维化基因的可能作用， 对广泛的纤维性疾病具有重要的潜在重要性 肝、肺和其他器官的疾病。

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.