Liver regeneration is a tightly regulated process of rapid, non-embryonic, non-neoplastic growth that is a paradigm for understanding other conditions of normal or altered growth regulation including tissue hypertrophy, wound healing, cancer, and possibly even normal or """"""""catch-up"""""""" childhood growth. The long term goal of this proposal is to elucidate the mechanisms by which growth stimulatory and growth inhibitory signals interact to control liver mass during regeneration and other conditions of liver growth. The underlying hypothesis is that a stimulus to liver growth also initiates a coupled inhibitory response. We show that both stimulatory and inhibitory growth factors are present in non-regenerating liver, and propose that partial hepatectomy (PH) alters the cell types that produce and respond to these factors and thereby alters the balance between signals to grow or arrest. The studies aim to define the growth factor mediated interactions among the component cells of liver with one another and with extrahepatic signals during regeneration. Using specific probes for TGF-Beta1, -Beta2, -Beta3, bFGF, TGF-alpha, and the EGF/TGF-alpha receptor, quantitative measurements of growth factor mRNA and peptide levels in tissues will be made in conjunction with in situ hybridization and immunohistochemical studies to localize growth factor producing cells, and define the changes that occur in the production or action of endogenous growth factors during regeneration. Isolated liver cells in culture will be used to study the regulation of growth factor production and action in hepatocytes, lipocytes, endothelial, and Kupffer cells. Exogenous growth factors and neutralizing antibodies will be administered to rats to establish changes in sensitivity to growth factor actions after PH and in the intact liver. Studies are proposed to test the hypothesis that a TGF-Beta-resistant state develops in regenerating liver, and to identify critical TGF-Beta-sensitive events in the hepatocyte cell cycle that could elucidate its mechanism(s) of action. The studies outlined here may be of particular clinical relevance to the pathophysiology of certain liver diseases that are characterized by abnormal cellular proliferation, as well as to the design of artificial livers and other organs, hepatic gene therapy for metabolic disorders, and liver preservation and transplantation.
