FETAL BRANCHED CHAIN AMINO ACID AND KETOACID METABOLISM

精确调节蛋白质合成和蛋白质分解是至关重要的 以维持正常的胎儿蛋白质同化率。虽然 胰岛素被认为是早期胎儿主要的生长激素 对胎儿蛋白质代谢的研究表明 胎儿的高胰岛素血症并不能减少蛋白质的分解。我们 假设IGF-I在胎儿中具有这一功能。 我们建议研究胰岛素样生长因子在血管内皮细胞生长中的作用。 胎儿蛋白动力学的慢性调节 导尿管胎羊。胎儿蛋白质动力学示踪建模，使用 标记的亮氨酸和苯丙氨酸将用于整体测定 胎儿输注胰岛素样物质时胎儿身体和后肢的变化 生长因子I 将调查以下具体目标： 1.观察IGF-I对氨基酸和蛋白质代谢的影响 在妊娠晚期的胎儿。重组人胰岛素样生长因子-L输液将 同时进行蛋白质合成速率的测定， 整个胎儿体内的分解、氧化和净堆积(通过 亮氨酸动力学)和胎儿后肢组织中反映骨骼的 肌肉，(通过苯丙氨酸动力学)。我们假设人胰岛素样生长因子-I会 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 不依赖于同时引起的胰岛素和氨基酸变化 浓度。胰岛素、氨基酸和葡萄糖将与 胰岛素样生长因子-I进入胎儿。动物在喂食时和一年后将被研究 延长产妇禁食时间。我们假设蛋白质分解的变化 将与没有胰岛素和氨基酸的研究动物相似，但 蛋白质合成速率和蛋白质堆积量将会增加。 3.测定胎儿亮氨酸水平变化的剂量效应 苯丙氨酸对循环IGF-I分级浓度的动力学。 研究将在喂食和禁食的动物身上进行，剂量反应 构造的曲线。循环总IGF-I浓度，以及 结合蛋白的浓度将被确定。我们假设 对蛋白质分解的剂量反应(IGF-I效应)将类似于 喂食和禁食动物，但氨基酸的积累(底物供应 效果)在喂食的动物中将在更大程度上增加。 4.确定全身性与组织局限性的相对重要性 IGF系统的变化。将检测特定组织中的IGF-I和 信使核糖核酸和蛋白质及ICFBP 1-4蛋白质；蛋白质合成率 将在相同的组织中被确定。我们假设分数 从禁食动物获得的组织合成速率将会降低， 并将与IGF-I的信息和蛋白质减少有关。在……里面 此外，我们假设组织IGF-I表达的变化将 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间比率。

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.