The long range goals of this laboratory are to understand and ultimately control both normal and abnormal cell growth in blood vessel walls. Platelet derived growth factor(s) (PDGF) release locally during hemostasis and thrombosis appear to influence both cell migration into blood vessel walls and to initiate the paracrine and perhaps the autocrine regulation of their growth. The product of the v-sis oncogene, p28v-sis, shares near identify with PDGF in its mitogenic activity and chemotactic potency and thus is well suited as a model to pursue the associated inflammatory and proliferative responses associated with thrombosis and hemostasis, and perhaps with the pathological process of atherosclerosis. It is planned to analyze cells which express PDGF-like proteins and to seek mechanisms and sites of activity whereby these proteins initiate DNA synthesis and cell proliferation, using techniques of cell biology, biochemistry, and molecular biology.
The specific aims are to analyze the processing of both the v-sis gene product and the PDGF cell surface receptor and to determine at which stage of processing the v-sis gene product may interact with the PDGF receptor as each is processed through the endoplasmic reticulum/Golgi complex and to determine whether the PDGF receptor is activated in SSV-transformed cells prior to expression at the cell surface. It is also planned to express cDNA clones of the PDGF A-chain a) to determine if the PDGF A-chain coupled to a strong promoter transforms Nr6 cells, b) to synthesize and purify A-chain homodimers for further study, c) to analyze the processing of the PDGF A-chain, and d) to determine if the A-chain interacts with the PDGF receptor. We also plan to isolate, sequence, and analyze the 5' upstream DNA sequences of the PDGF A-chain gene and to analyze the regulation of the PDGF receptor at the level of gene transcription and translation, and at the level of expression and degradation of the receptor protein at the cell surface. These experiments seek to fill gaps in the existing knowledge of the basic mechanisms whereby growth factors stimulate normal cell proliferation and perhaps play roles in the pathological processes of atherosclerosis and fibrotic diseases, with the long range goal of providing approaches to rational therapeutic means for controlling these processes in appropriate situations.
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