Nutritional Regulation of Fetal Liver Development

描述(由申请人提供)：这是一个项目的续展申请，该项目的重点是调节妊娠晚期胎鼠的肝脏发育。前一个周期的总体目标是研究肝脏中的胰岛素信号通路，以检验孕期母亲限制热量会导致胎儿肝脏胰岛素抵抗，以及这种抵抗会持续到出生后晚期的假说。几次意想不到的观察改变了项目的重点。首先，由于胰岛素信号在近端和远端的联合变化，正常妊娠晚期胎儿的肝细胞存在严重的胰岛素抵抗。因此，我们认为胎儿宫内发育迟缓与胎儿肝脏胰岛素抵抗有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出生后肝脏或骨骼肌近端胰岛素信号的改变无关。这些负面结果让我们把注意力集中在一个关键问题上：如果胰岛素不是调节IUGR胎儿肝脏生长减退的媒介，那是什么？我们选择从增殖所需的有丝分裂信号的两个目标--细胞周期和蛋白质翻译机制--向后工作。随后的研究描述了正常妊娠大鼠、晚期妊娠大鼠和饮食受限母亲的IUGR胎儿的胎儿肝细胞生长调节机制。我们假设了营养感应蛋白激酶mTOR(雷帕霉素的哺乳动物靶标)的中心作用。结果导致了目前的假设，即胎儿中的营养供应通过mTOR信号转导核糖体和细胞周期来调节胎儿肝细胞的增殖。这一假设将在以下具体目标中得到检验。具体目的1：确定在妊娠晚期胎肝细胞中调节mTOR信号转导核糖体生物发生、蛋白质翻译和细胞周期进展的营养因子。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营养信号的差异，重点是我们先前观察到的在体胎儿肝细胞不同于成人肝细胞，对mTOR抑制剂雷帕霉素的生长抑制作用具有抵抗力。我们希望这些研究能加深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、肝癌变和肝干细胞生物学。

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.