REGULATION OF PDGF RECEPTORS

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Platelet-derived growth factor (PDGF) is a polypeptide growth factor which was originally isolated from blood platelets. Release of PDGF was proposed to play a beneficial role in wound healing and a pernicious role in the etiology of atherogenesis. PDGF is now known to be secreted by many different cell types and to be the proto-oncogene of two mammalian retroviruses. These observations have stimulated much current investigation and speculation on the possibility that PDGF might be involved in additional processes of normal tissue development and remodeling, as well as in oncogenic transformation. Most hypotheses about the functions of PDGF treat the PDGF receptor as though its expression were uniform and unchanging, with the functions of PDGF being determined entirely through regulation of production or release of PDGF. We propose to test the hypotheses that: (1) PDGF receptor expression is regulated during development and during acute tissue responses to stimuli. (2) This regulation of PDGF receptor expression plays an important role in determining the biological functions of PDGF. To test these hypotheses we will first determine which cells express PDGF receptors in normal adult tissues, how this pattern is established during embryogenesis, and how it is altered in response to stimuli. Expression of both receptor subunits will be determined since our initial evidence suggests that the two subunits are independently regulated and may serve somewhat different functions in vivo. Cell culture models of precesses displaying regulation of receptor expression will be further developed to permit investigation into the molecular mechanisms through which receptor expression is regulated. Finally, we will attempt to confirm hypotheses about the biological functions of PDGF by experimentally manipulating receptor expression in culture and in vivo.