Nutritional Regulation of Fetal Liver Development

描述（由申请人提供）：这是一个项目的更新申请，该项目专注于妊娠晚期胎鼠肝脏发育的调节。前一个周期的总体目的是检查肝脏中的胰岛素信号通路，以验证怀孕期间母体热量限制导致胎儿肝脏胰岛素抵抗的假设，并且这种抵抗持续到出生后后期。几个意想不到的观察结果改变了项目的重点。首先，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产生了严重的胰岛素抵抗。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出生后肝脏或骨骼肌近端胰岛素信号的改变无关。这些阴性结果使我们关注一个关键问题：如果胰岛素没有介导IUGR胎儿的肝脏生长减弱，那是什么呢？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往回工作。随后的研究确定了正常、妊娠晚期大鼠和饮食限制母亲的IUGR胎儿的胎儿肝细胞生长调节机制。我们假设营养感应蛋白激酶mTOR（雷帕霉素的哺乳动物靶点）起着核心作用。这些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的增殖。这一假设将在以下具体目标中进行检验。特异性目标1：确定在妊娠晚期胎儿肝细胞中调节mTOR信号对核糖体生物发生、蛋白质翻译和细胞周期进展的营养因子。具体目标2：确定这种营养信号传导的机制。特异性目标3：表征胎儿和成人肝细胞之间营养信号的差异，重点关注我们之前的观察，即胎儿肝细胞在体内，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各个领域，包括肝脏对肝损伤的反应、肝癌发生和肝干细胞生物学。

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.