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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29DK042485-04
Application #
3464120
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1990-06-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Bhora, F Y; Kothary, P C; Imanishi, H et al. (1994) Vasopressin stimulates DNA synthesis in cultured rat hepatocytes. J Surg Res 57:706-10
Raper, S E; Kothary, P C; Kokudo, N et al. (1993) Hepatectomy impairs hepatic processing of somatostatin-14. Am J Surg 165:89-94;discussion 94-5
Raper, S E; Kothary, P C; DelValle, J (1992) Identification and partial characterization of a somatostatin-14 binding protein on rat liver plasma membranes. Hepatology 16:433-9
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Kokudo, N; Kothary, P C; Eckhauser, F E et al. (1992) Transforming growth factor-alpha (TGF-alpha) improves hepatic DNA synthesis after hepatectomy in cirrhotic rats. J Surg Res 52:648-55
Kokudo, N; Kothary, P C; Eckhauser, F E et al. (1991) Inhibitory effects of somatostatin on rat hepatocyte proliferation are mediated by cyclic AMP. J Surg Res 51:113-8
Raper, S E; Kothary, P C; Kokudo, N (1991) Somatostatin-14 blocks the hepatotrophic effects of insulin in the rat. J Surg Res 50:386-90
Raper, S E; Kothary, P C; Kokudo, N et al. (1991) The liver plays an important role in the regulation of somatostatin-14 in the rat. Am J Surg 161:184-9