Nutritional Regulation of Fetal Liver Development

描述（申请人提供）：这是一份关于妊娠晚期胎鼠肝脏发育调控的项目延续申请。上一个周期的总体目标是检查肝脏中的胰岛素信号通路，以检验妊娠期母体热量限制诱导胎儿肝脏胰岛素抵抗以及这种抵抗持续到出生后晚期的假设。几个意想不到的观察结果改变了该项目的重点。第一个是正常妊娠晚期胎儿的肝细胞由于胰岛素信号的近端和远端变化而具有严重的胰岛素抵抗。因此，我们关于IUGR与胎儿肝脏胰岛素抵抗相关的假设是站不住脚的。在进一步的研究中，我们发现胎儿生长迟缓与产后肝脏或骨骼肌近端胰岛素信号传导的改变无关。这些负面的结果使我们关注一个关键问题：如果胰岛素不是介导IUGR胎儿肝脏生长减弱，那是什么？我们选择从增殖所需的促有丝分裂信号传导的两个靶点，即细胞周期和蛋白质翻译机制进行反向工作。随后的研究特征的胎儿肝细胞生长调节机制，在正常，妊娠晚期大鼠和IUGR胎儿的饮食限制的母亲。我们假设营养敏感蛋白激酶mTOR（雷帕霉素的哺乳动物靶标）的核心作用。结果导致了目前的假设，即胎儿的营养可利用性通过mTOR信号传导到核糖体和细胞周期来调节胎儿肝细胞增殖。这一假设将在以下具体目标中得到检验。具体目标1：鉴定调节mTOR信号传导至妊娠晚期胎肝细胞中核糖体生物合成、蛋白质翻译和细胞周期进程的营养因子。具体目标2：确定这种营养信号的机制。具体目标3：描述胎儿和成人肝细胞之间营养信号传导的差异，重点关注我们先前的观察结果，即体内胎儿肝细胞与成人肝细胞不同，对mTOR抑制剂雷帕霉素的生长抑制作用具有抗性。我们希望这些研究能增加我们对胎儿营养状况影响肝脏生长和成熟的机制的理解。此外，我们预计我们的发现将涉及肝脏生物学的不同领域，包括肝脏对肝损伤的反应，肝癌发生和肝脏干细胞生物学。

DESCRIPTION (provided by applicant): 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.