FETAL BRANCHED CHAIN AMINO ACID AND KETOACID METABOLISM

蛋白质合成和蛋白质分解的精确调节至关重要 维持正常的胎儿蛋白同化率虽然 胰岛素被认为是早期胎儿生长激素， 胎儿蛋白质代谢的研究表明， 胎儿的高胰岛素血症并不减少蛋白质的分解。我们 假设IGF-I在胎儿中具有这种功能。 我们建议研究胰岛素样生长因子在 胎儿蛋白动力学的调节 插入导管的胎儿羔羊。胎儿蛋白动力学的示踪剂建模，使用 标记的亮氨酸和苯丙氨酸，将用于确定在整个 在胎儿体内和胎儿后肢期间输注胰岛素样 生长因子I 将研究以下具体目标： 1.评估IGF-I对氨基酸和蛋白质代谢的影响 在妊娠晚期的胎儿中。重组人IGF-I输注将是 进行，同时测定蛋白质合成速率， 分解，氧化，和净增长在整个胎儿身体（由 亮氨酸动力学）和胎儿后肢组织中，反映骨骼 肌肉，（苯丙氨酸动力学）。 我们假设rhIGF-I 导致蛋白质分解减少。 2.为了确定胎儿亮氨酸动力学的变化是否是 不依赖于同时诱导的胰岛素和氨基酸的变化 浓度的胰岛素、氨基酸和葡萄糖将与 IGF-I进入胎儿。动物将在喂食时和喂食后进行研究。 长期的母亲禁食我们假设蛋白质分解的变化 将类似于没有胰岛素和氨基酸的动物，但 蛋白质的合成速率和蛋白质的增加会增加。 3.为了确定胎儿亮氨酸变化的剂量反应， 苯丙氨酸动力学与分级循环IGF-I浓度的关系。 将在进食和禁食动物中进行研究，并研究剂量-反应关系。 曲线构造总循环IGF-I浓度，和 将测定结合蛋白的浓度。我们假设 蛋白质分解的剂量反应（IGF-I效应）将类似于 喂养和禁食的动物，但氨基酸增长（底物供应 效果）将在喂养的动物中更大程度地增加。 4.确定全身与组织受限的相对重要性 IGF系统的变化。将测定特定组织的IGF-I， mRNA和蛋白质以及ICFBP 1-4蛋白质;蛋白质合成率分数 将在相同的组织中测定。我们假设分数 从禁食动物获得的组织中的合成速率将降低， 并将与IGF-I的信息和蛋白质减少相关。在 此外，我们假设组织中IGF-I表达的改变将 与部分蛋白质合成中的差异反应相关 禁食诱导的底物剥夺的组织中的比率。

Precise regulation of protein synthesis and protein breakdown is critical to maintaining normal rates of fetal protein assimilation. Although insulin is regarded as the primary fetal growth hormone our earlier investigations of fetal protein metabolism demonstrated that hyperinsulinemia in the fetus does not diminish protein breakdown. We hypothesize that IGF-I has this function in the fetus. We propose to investigate the role of insulin-like growth factors in the regulation of fetal protein kinetics utilizing the chronically catheterized fetal lamb. Tracer modeling of fetal protein kinetics, using labeled leucine and phenylalanine, will be used to determine in the whole fetal body and in the fetal hindlimb during fetal infusion of insulin-like growth factor I. The following specific aims will be investigated: 1. To assess the effect of the IGF-I on amino acid and protein metabolism in the late gestation fetus. Recombinant human IGF-l infusions will be performed, with simultaneous determination of rates of protein synthesis, breakdown, oxidation, and net accretion in the whole fetal body (by leucine kinetics) and in fetal hindlimb tissue, reflective of skeletal muscle, (by phenylalanine kinetics). We hypothesize that rhIGF-I will result in diminished protein breakdown. 2. To determine whether the changes seen in fetal leucine kinetics are independent of simultaneously induced changes in insulin and amino acid concentrations. Insulin, amino acids, and glucose will be co-infused with IGF-I into the fetus. Animals will be studied when fed and after a prolonged maternal fast. We hypothesize that changes in protein breakdown will be similar to animals studied without insulin and amino acids, but that protein synthetic rates and protein accretion will be increased. 3. To determine the dose response of changes in fetal leucine and phenylalanine kinetics to graded circulating IGF-I concentrations. Studies will be conducted in fed and fasted animals, and dose-response curves constructed. Total circulating IGF-I concentration, and concentrations of binding proteins will be determined. We hypothesize that the dose response for protein breakdown (IGF-I effect) will be similar in fed and fasted animals, but that amino acid accretion (substrate supply effect) will be increased to a greater extent in the fed animals. 4. To determine the relative importance of systemic vs. tissue limited changes in the IGF system. Specific tissues will be assayed for IGF-I and mRNA and protein and ICFBP 1-4 protein; fractional protein synthetic rates will be determined in the same tissues. We hypothesize that fractional synthetic rates will be decreased in tissues obtained from fasted animals, and will be associated with decreased message and protein for IGF-I. In addition, we hypothesize that alterations in tissue IGF-I expression will be correlated with differential responses in fractional protein synthetic rate among tissues to fasting induced substrate deprivation.