Fetal Glucose and Amino Acid Deprivation

胎儿宫内生长受限(IUGR)是一种常见的妊娠疾病，它扰乱了胎儿的新陈代谢和生长，导致胎儿、新生儿和成人的发病率和死亡率显著增加。胎儿宫内发育迟缓的发生机制尚不清楚，胎儿代谢如何在胎儿宫内发育迟缓时发生改变，尤其是与底物利用能力和胰岛素敏感性的适应有关。该计划的目标是确定IUGR胎儿胰岛素作用和底物利用改变的生理、细胞和分子机制，目的是纠正子宫内的改变。拟议的研究将检验IUGR环境的假设：a)增加葡萄糖清除和胰岛素敏感性，以及b)通过扰乱特定的下游细胞成分胰岛素信号级联而降低氨基酸代谢，从而导致蛋白质合成减少和胎儿生长。我们将使用体内和体外方法在我们的母牛怀孕期间产生IUGR的牛模型中验证这一假说。具体目标1将确定在IUGR胎儿中，血糖和胰岛素调节胎儿葡萄糖利用的能力是否增加，以及GLUT1和4基因转录、蛋白质数量和/或易位的变化是否与调节骨骼肌葡萄糖代谢的葡萄糖和/或胰岛素信号转导有关，包括胰岛素受体、IRS-1和PI3-激酶途径的表达和磷酸化增加。具体目标3将确定IUGR胎儿血浆氨基酸和胰岛素调节氨基酸利用的能力是否减弱。特定目标5将确定在特定目标1-4中发现的异常底物利用和/或胰岛素作用是否可以通过体内母体和/或胎儿输注葡萄糖、氨基酸或胰岛素来改善，从而为改善IUGR胎儿异常代谢、发育和生长提供更合理的治疗方法。

Intrauterine growth restriction (IUGR) is a common disorder of pregnancy that disrupts fetal metabolism and growth, leading to marked increase in fetal, neonatal, and adult morbidity and mortality. Mechanisms for IUGR are inadequately understood, and there is confusion about how fetal metabolism is altered in IUGR, particularly regarding adaptations of substrate utilization capacity and insulin sensitivity. The goal of this program is to determine physiological, cellular, and molecular mechanisms underlying altered insulin action and substrate utilization in IUGR fetuses, with an aim to correcting the changes in utero. The proposed studies will test the hypothesis that the IUGR environment: a) increases glucose clearance and insulin sensitivity, and b) decreases amino acid metabolism by disrupting specific downstream cellular components insulin signaling cascades that lead to decreased protein synthesis and fetal growth. We will use in vivo and in vitro methods to test this hypothesis in our bovine model of IUGR produced by maternal during pregnancy. Specific aim 1 will determine if the capacity for plasma glucose and insulin to regulate fetal glucose utilization is increased and if changes in GLUT1 and 4 gene transcription, protein amount, and/or translocation account for altered glucose and/or insulin signal transduction that regulates glucose metabolism in skeletal muscle, including expression and phosphorylation of the Insulin Receptor, IRS-1, and PI3-kinase pathway, is increased in the IUGR fetus. Specific aim 3 will determine if the capacity for plasma amino acids and insulin to regulate amino acid utilization is diminished in IUGR fetuses. Specific aim 5 will determine if abnormal substrate utilization and/or insulin action discovered in Specific Aims 1-4 can be ameliorated by in vivo maternal and/or fetal infusions of glucose, amino acids, or insulin, thereby providing more rational therapeutic approaches to improve abnormal metabolism, development, and growth in fetuses with IUGR.