The limitation of substrate availability to the fetus is a cause of intrauterine growth retardation (IUGR). The fetal response to substrate limitation is an adaptive one, with controlled tissue- and organ-specific effects on growth and differentiation. The purpose of this proposal is to study mechanisms regulating fetal hepatic growth. Specifically, the roles of the peptide transforming growth factors TGF-alpha and TGF-beta in the control of hepatic growth in normal and growth-retarded fetuses will be studied. The model of maternal dietary restriction during the last four days of gestation in the rat will be used to induce IUGR. Food will be withdrawn from the mother for 24, 48, 72 or 96 hours prior to cesarean delivery at term. Results will be compared to normal fetuses studied during the period of rapid fetal growth prior to term, i.e., on days 17, 18, 19, 20 or 21 of gestation. The hypothetical regulatory scheme which will be tested is that fetal substrate availability leads to diminished growth through perturbation of the TGF-alpha and TGF-beta systems. Furthermore, changes mediated through reversible phosphorylation of proteins will be the central focus. Preliminary studies in the model of partial hepatectomy in the adult rat have shown that hepatocellular proliferation is stimulated by TGF-alpha, the liver homologue of epidermal growth factor (EGF). Its action is mediated through binding to EGF receptors and, presumably, stimulation of EGF receptor-associated tyrosine kinase activity. Conversely, in the regenerating rat liver, proliferation is opposed by TGF-beta acting through its own high-affinity receptors. TGF-beta action may be mediated by protein phosphotyrosine phosphatase. In addition, it is known that the EGF receptor kinase is regulated by threonine phosphorylation by protein kinase C. Thus, the present proposal will examine the following in livers from normal and growth-retarded fetal rats: [1] Changes in TGF- alpha and TGF-beta secretion (by monitoring mRNA for these hormones); [2] TGF-alpha and TGF-beta receptor binding; [3] Membrane-associated (EGF- receptor) tyrosine kinase and protein phosphotyrosine phosphatase activities, and; [4] Membrane-associated serine/threonine kinase (protein kinase C) and phosphatase activities. It is anticipated that the changes which occur in IUGR will provide insight into the regulation of fetal hepatic growth.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD024455-02
Application #
3325046
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1989-04-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Rhode Island Hospital (Providence, RI)
Department
Type
DUNS #
161202122
City
Providence
State
RI
Country
United States
Zip Code
02903
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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