Our purpose is to use cell culture and whole animal models of hepatic regeneration and carcinogenesis in order to elucidate the role of the alpha-1 adrenergic receptor in regulation of normal and neoplastic cell growth. We have recently shown that the alpha-1 adrenergic receptor stimulates DNA synthesis in hepatocytes in culture and that this response is mediated by heterologous regulation of the EGF receptor. Stimulation of DNA synthesis by the alpha-1 receptor agonist norepinephrine has also been recently shown to operate for many other cell types. The studies proposed will probe into the role of the alpha-1 receptor as a regulator whose function is required or altered in normal or neoplastic hepatoproliferative states. The development of early neoplastic foci under different states of alpha-1 function (or blockade) and the response of such lesions developed under established carcinogenesis protocols to the mitogenic effects of the alpha-1 receptor will be studied. Several previous studies also suggest that the proteins encoded by the ras oncogene family are identical to the GTP-binding proteins of a calcium mobilizing receptor that regulates cell growth. In view of the fact that the alpha-1 receptor is such a receptor and the identity of its associated GTP-binding proteins is not known, studies will be conducted to test the hypothesis that the Ras protein family or some of its members may be identical to the GTP binding protein associated with the alpha-1 receptor.
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