The initiating event in atherosclerosis is now thought to be a subtle process of endothelial dysfunction. Secretory products produced by dysfunctional endothelial might initiate the migration and proliferation of smooth muscle cells. This model for atherogenesis has been supported by observations that endothelial cells can produce a platelet-derived growth factor (PDGF)-like mitogen. The underlying assumption behind these studies has been that a crucial initial step in atherogenesis consists of increased production of PDGF-like mitogens by endothelium. If this model is correct, then understanding the structure and regulatory mechanisms used by the endothelial cell to control PDGF production would be important advances in the understanding of atherogenesis. PDGF is now know to be a dimer of two chains, designated A and B. Endothelial cDNAs for the A and B chains have been obtained and used to define both the A and B chain genes. This structural information forms the basis of this proposal in which the regulatory mechanisms used by the endothelial cell in controlling expression of these genes will be defined. Regulation of the expression of PDGF by endothelial cells may occur at both the transcriptional and translational levels. In the proposed studies, the transcriptional units of the A and B chain genes will be further defined by characterizing the functional elements in the promoters and defining novel transcriptional regulatory factors. By localizing the functional cis-acting elements in the PDGF A and B chain promoters, it may be possible to elucidate the normal transcriptional control of the gene, as well as mechanisms that may activate it in certain pathologic settings. Also, the identification of novel trans-acting factors interacting with the A and B chain genes may provide new insights into the process of endothelial dysfunction. It is clear that the translation of the PDGF B chain transcript is a relatively inefficient process and therefore a stage at which the expression of the gene could be regulated. The proposed studies will further characterize the translational control of PDGF expression by defining the elements in the 5'untranslated region of the A and B chain genes which inhibit translation and identifying novel putative RNA binding factors regulating this process. Understanding these regulatory events may provide important insights into the control of PDGF expression and may permit the development of new strategies for identifying patients at risk of forming atherosclerotic lesions.
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