Recent advances in molecular biology have shown that the products of the cellular homologs of retroviral transforming genes are important regulators of cell growth and behavior in normal as well as malignant cells. We propose to study the role of these products in vascular endothelial cells. We will initially focus upon c-sis, the cellular homolog of the simian sarcoma virus transforming gene (v-sis), which encodes for one chain of platelet-derived growth factor (PDGF) because endothelial cells in culture synthesize PDGF-like mitogens. In the context of vessel wall, c-sis expression has generated intense interest since PDGF is known to be mitogenic for smooth muscle cells and chemotactic for leukocytes, key elements in the generation of an atherosclerotic plaque. First we will determine the complete structure of c-sis mRNA cloned from human endothelium and elaborate the regulatory mechanisms utilized by the endothelial cell in controlling the production of the c-sis product. These experiments are based upon our isolation and sequence analysis of a 2.1 kb v-sis homologous cDNA clone from human endothelial cells, and provide the first opportunity to study the structure of sis as transcribed by a normal (untransformed) cell. We propose to extend our studies to regulatory sequences associated with the c-sis gene. We also plan to identify and characterize mRNA's encoding the less cis-homologous chain of PDGF. Additionally we will use expression systems for a structure/function analysis of both c-sis regulatory sequences and the c-sis encoded polypeptide. Understanding the structure of PDGF produced by endothelial cells may permit construction of PDGF analogs which may be clinically useful in altering atherogenic or neovascular processes. In a second project, we will investigate the role of other tranforming gene homologs in the control of endothelial cell growth by using pseudotyped amphotropic retroviruses to introduce exogenous retroviral transforming genes into cultured endothelial cells. We propose to correlate modifications of endothelial cell behavior with expression of both exogeneous and endogenous cellular tranforming gene homologs. By comparing the retrovirus modified cells with normal endothelial cells we will infer mechanisms for normal growth and phenotypic conrol, generating specific hypotheses to be tested.

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National Heart, Lung, and Blood Institute (NHLBI)
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Brigham and Women's Hospital
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