This application is for continuation of a project aimed at investigating the mitogenic signal transduction mechanisms involved in hepatocyte proliferation late in gestation in the rat. The proposal is based on results of this project obtained during the last cycle which demonstrated that fetal rat hepatocyte proliferation in vitro and in vivo occurs without activation of a major mitogenic signaling pathway involving Mitogen Activated Protein Kinases (MAPKs). While this pathway was intact and could be activated by mitogens in cultured fetal rat hepatocytes, fetal hepatic MAPKs could not be activated in vivo by the intraperitoneal administration of Epidermal Growth Factor (EGF) to intact fetuses. This """"""""uncoupling' occurred even though signal initiation by the EGF receptor tyrosine kinase was intact. In contrast to hepatic MAPK regulation, a parallel pathway involving Jun N-terminal Kinases (JNKs) was found to be active in fetal (but not adult) liver 171 vivo under basal conditions. Based on these findings, we propose the following specific aims: [1] To determine the mechanisms responsible for uncoupling of hepatic MAP kinase activation in the late gestation rat, and [2] To examine the significance of constitutive fetal hepatic JNK activity as it relates to regulation of gene expression. The overall strategy for these studies will be to carry out in vitro experiments using cultured fetal rat hepatocytes to identify potential mechanisms related to MAPK uncoupling and JNK-dependent control of growth-regulating genes. We will then carry out parallel comparative in vivo studies by examining the response to direct intraperitoneal injection of growth factors or insulin to the fetal rat. Key areas of emphasis will be the developmental aspects of the expression and function of constituents of hepatic mitogenic signaling pathways, JNK- dependent transcription factor (AP-I, ATF-2) regulation and JNK- dependent control of growth-regulating gene expression. We anticipate that our results will have implications for the physiology and pathophysiology of perinatal hepatocyte growth and hepatic development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Rhode Island Hospital (Providence, RI)
United States
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Sanders, Jennifer A (2017) Late Gestation Fetal Hepatocytes for Liver Repopulation in the Rat. Methods Mol Biol 1506:45-60
Boylan, Joan M; Francois-Vaughan, Heather; Gruppuso, Philip A et al. (2017) Engraftment and Repopulation Potential of Late Gestation Fetal Rat Hepatocytes. Transplantation 101:2349-2359
Adebayo Michael, Adeola O; Ahsan, Nagib; Zabala, Valerie et al. (2017) Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma. Oncotarget 8:26041-26056
Tan, Ek Khoon; Shuh, Maureen; Francois-Vaughan, Heather et al. (2017) Negligible Oval Cell Proliferation Following Ischemia-Reperfusion Injury With and Without Partial Hepatectomy. Ochsner J 17:31-37
Boylan, Joan M; Sanders, Jennifer A; Gruppuso, Philip A (2016) Regulation of fetal liver growth in a model of diet restriction in the pregnant rat. Am J Physiol Regul Integr Comp Physiol 311:R478-88
Francois-Vaughan, Heather; Adebayo, Adeola O; Brilliant, Kate E et al. (2016) Persistent effect of mTOR inhibition on preneoplastic foci progression and gene expression in a rat model of hepatocellular carcinoma. Carcinogenesis 37:408-419
Gruppuso, Philip A; Sanders, Jennifer A (2016) Regulation of liver development: implications for liver biology across the lifespan. J Mol Endocrinol 56:R115-25
Huse, Susan M; Gruppuso, Philip A; Boekelheide, Kim et al. (2015) Patterns of gene expression and DNA methylation in human fetal and adult liver. BMC Genomics 16:981
Boylan, Joan M; Salomon, Arthur R; Tantravahi, Umadevi et al. (2015) Adaptation of HepG2 cells to a steady-state reduction in the content of protein phosphatase 6 (PP6) catalytic subunit. Exp Cell Res 335:224-37
Boylan, Joan M; Sanders, Jennifer A; Neretti, Nicola et al. (2015) Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR). Am J Physiol Regul Integr Comp Physiol 309:R22-35

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