Fetal Glucose and Amino Acid Deprivation

宫内生长受限（IUGR）是一种常见的妊娠障碍，它会破坏胎儿的代谢和生长，导致胎儿、新生儿和成人的发病率和死亡率显著增加。IUGR的机制尚不清楚，胎儿代谢在IUGR中是如何改变的，特别是关于底物利用能力和胰岛素敏感性的适应，这一点尚不清楚。该项目的目的是确定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变化。拟议的研究将验证以下假设：IUGR环境：a)增加葡萄糖清除率和胰岛素敏感性，b)通过破坏特定的下游细胞成分胰岛素信号级联反应减少氨基酸代谢，导致蛋白质合成和胎儿生长减少。我们将使用体内和体外方法在我们的牛模型中验证这一假设，该模型是由母体在怀孕期间产生的IUGR。具体目的1将确定血浆葡萄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、蛋白量和/或易位的变化是否解释了IUGR胎儿中调节骨骼肌葡萄糖代谢的葡萄糖和/或胰岛素信号转导的改变，包括胰岛素受体、IRS-1和pi3激酶途径的表达和磷酸化是否增加。具体目的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。特异性目的5将确定特异性目的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母体和/或胎儿体内输注葡萄糖、氨基酸或胰岛素来改善，从而提供更合理的治疗方法来改善IUGR胎儿的异常代谢、发育和生长。

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.