This research proposal is directed at investigating, on a fundamental level, the antiproliferative effects of somatostatin (SRIF) on liver. An improved understanding of the signals that control the inhibition of cellular growth will have broad implications for both benign and malignant disease. Such pathologic processes would include surgical resectional therapy, liver transplantation, liver failure, primary and metastatic liver tumors.
The specific aims of this proposal are: 1) to determine the effects of SRIF on liver regeneration during basal and stimulated conditions; 2) to study the binding of SRIF to membranes from intact liver and hepatocytes; 3) to biochemically characterize the SRIF binding proteins and show they are receptors; 4) to identify the mechanism of SRIF metabolism by the liver, and how SRIF metabolism is altered by hepatectomy. Information obtained as a result of achieving the specific aims will be highly significant in several areas: 1) identification of a new antiproliferative role for SRIF; 2) rigorous identification and biochemical characterization of the hepatic SRIF receptor; 3) advancement of the understanding of the cellular mechanisms of SRIF action; and 4) acquisition of knowledge about the role of the liver in SRIF metabolism. Preliminary data collected by the principal investigator for this research proposal includes information on: 1) inhibition of hepatocyte proliferation by SRIF; 2) specific saturable binding of SRIF to rat liver membranes and isolated hepatocytes; 3) a monomeric 70,000 molecular weight liver membrane protein which specifically binds SRIF; 4) regulation of SRIF binding of hepatocytes by guanine nucleotides; and 5) evidence for the hepatic uptake and biliary excretion of radiolabelled SRIF. The experimental design of the research proposal will systematically study: 1) the effects of SRIF on hepatocyte proliferation; 2) characterization of functional and structural aspects of the hepatic SRIF receptor; 3) the role of G proteins in hepatic SRIF receptor signal transduction; and 4) the mechanisms of hepatic uptake and intracellular processing of SRIF.
