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 Food will be withdrawn from the mother for 24, 48, 72 or 96 hours prior to cesarean delivery at term.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.
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