The goal of this proposal is to investigate the role of a putative liver-specific growth factor, hepatic stimulator substance (HSS), in liver regeneration and compare its effects with other mitogens, e.g., insulin like growth factors or transforming growth factors. Specific experiments will be performed as follows: 1) In vitro cell cycle specific effects of HSS and other mitogens in defined culture conditions will be characterized with HSS responsive, putative liver stem cells of epithelial origin (FNRL). Cell cycle curves will be generated by (3H)-thymidine incorporation and cell cycle subpopulations will be analyzed by flow cytometry. To determine which cell subpopulation is specifically responsive to HSS, GO/GI, S, or G2/M phase cells will be purified by centrifugal elutriation and exposed to mitogens. Simultaneous analysis will be performed of cell cycle related gene expression (e.g., c-fos, c-myc, c-Ha-ras). In vivo experiments in rats will determine whether HSS induces similar changes in gene expression. 2) To study whether HSS induces early events in membrane signal transduction, as opposed to later events such as nuclear gene activation, Na+ and Ca++ ion fluxes will be determined by NMR spectroscopy and tyrosine kinase activation will be determined by a peptide phosphorylation assay. 3) Whether HSS enhances in vivo proliferation of hepatocytes, or hepatocyte precursor cells with or without an introduced albumin gene, will be determined by transplanting HSS pretreated cells, or by administering HSS following transplantation into normal and analbuminemic rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK001909-02
Application #
3080791
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Gupta, S; Rajvanshi, P; Aragona, E et al. (1999) Transplanted hepatocytes proliferate differently after CCl4 treatment and hepatocyte growth factor infusion. Am J Physiol 276:G629-38
Rajvanshi, P; Bhargava, K K; Afriyie, M et al. (1998) Human serum albumin microspheres approximate initial organ-specific biodistributions of transplanted hepatocytes and are effective cell surrogates for safety studies. Cell Transplant 7:275-83
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Rajvanshi, P; Kerr, A; Bhargava, K K et al. (1996) Efficacy and safety of repeated hepatocyte transplantation for significant liver repopulation in rodents. Gastroenterology 111:1092-1102
Lee, C D; Ott, M; Thyagarajan, S P et al. (1996) Phyllanthus amarus down-regulates hepatitis B virus mRNA transcription and replication. Eur J Clin Invest 26:1069-76
Lu, B; Gupta, S; Federoff, H (1995) Ex vivo hepatic gene transfer in mouse using a defective herpes simplex virus-1 vector. Hepatology 21:752-9
Sigal, S H; Gupta, S; Gebhard Jr, D F et al. (1995) Evidence for a terminal differentiation process in the rat liver. Differentiation 59:35-42

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