This is an application for renewal of a project that has focused on regulation of liver development in the late gestation fetal rat. The overall aim of the previous cycle was to examine insulin signaling pathways in liver to test the hypotheses that maternal caloric restriction during gestation induces fetal hepatic insulin resistance, and that this resistance persists into late postnatal life. Several unexpected observations altered the focus of the project. The first was that hepatocytes in normal, late gestation fetuses are profoundly insulin resistant due to combined proximal and distal changes in insulin signaling. Thus, our hypothesis that IUGR would be associated with fetal hepatic insulin resistance was untenable. In further studies, we found that fetal growth retardation was not associated with altered hepatic or skeletal muscle proximal insulin signaling during postnatal life. These negative results led us to focus on a key question: If insulin is not mediating the attenuated liver growth in the IUGR fetus, what is? We elected to work backwards from two targets of mitogenic signaling that are required for proliferation, the cell cycle and the protein translational machinery. Ensuing studies characterized fetal hepatocyte growth regulating mechanisms in the normal, late gestation rat and in the IUGR fetus of a diet restricted mother. We hypothesized a central role for the nutrient-sensing protein kinase, mTOR (the mammalian target of rapamycin). Results led to the present hypothesis that nutrient availability in the fetus regulates fetal hepatocyte proliferation through mTOR signaling to the ribosome and the cell cycle. This hypothesis will be tested in the following specific aims.
Specific Aim 1 : Identify the nutritional factors that modulate mTOR signaling to ribosomal biogenesis, protein translation and cell cycle progression in late gestation fetal hepatocytes.
Specific Aim 2 : Determine the mechanisms for this nutrient signaling.
Specific Aim 3 : Characterize the differences in nutritional signaling between fetal and adult hepatocytes, focusing on our prior observation that fetal hepatocytes in vivo, unlike adult hepatocytes, are resistant to the growth inhibitory effects of the mTOR inhibitor, rapamycin. We expect these studies to add to our understanding of mechanisms by which fetal nutritional status affects liver growth and maturation. Furthermore, we anticipate that our findings will relate to diverse areas of liver biology, including the hepatic response to liver injury, hepatic carcinogenesis, and liver stem cell biology. ? ?
| Sanders, Jennifer A; Schorl, Christoph; Patel, Ajay et al. (2012) Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion. BMC Physiol 12:1 |
| Gruppuso, Philip A; Boylan, Joan M; Sanders, Jennifer A (2011) The physiology and pathophysiology of rapamycin resistance: implications for cancer. Cell Cycle 10:1050-8 |
| Jimenez, Rosa H; Lee, Ju-Seog; Francesconi, Mirko et al. (2010) Regulation of gene expression in hepatic cells by the mammalian Target of Rapamycin (mTOR). PLoS One 5:e9084 |
| Kim, Mimi S; Wu, Ke Ying; Auyeung, Valerie et al. (2009) Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. Am J Physiol Endocrinol Metab 296:E1374-82 |
| Phornphutkul, Chanika; Lee, Mark; Voigt, Cliff et al. (2009) The effect of rapamycin on bone growth in rabbits. J Orthop Res 27:1157-61 |
| Jimenez, Rosa H; Boylan, Joan M; Lee, Ju-Seog et al. (2009) Rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines. PLoS One 4:e7373 |
| Phornphutkul, Chanika; Wu, Ke-Ying; Auyeung, Valerie et al. (2008) mTOR signaling contributes to chondrocyte differentiation. Dev Dyn 237:702-12 |
| Gruppuso, Philip A; Tsai, Shu-Whei; Boylan, Joan M et al. (2008) Hepatic translation control in the late-gestation fetal rat. Am J Physiol Regul Integr Comp Physiol 295:R558-67 |
| Sanders, Jennifer A; Lakhani, Alisha; Phornphutkul, Chanika et al. (2008) The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats. Am J Physiol Cell Physiol 295:C406-13 |
| Yoo, Sunny J-S; Jimenez, Rosa H; Sanders, Jennifer A et al. (2008) The alpha4-containing form of protein phosphatase 2A in liver and hepatic cells. J Cell Biochem 105:290-300 |
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