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HORMONAL REGULATION OF NEONATAL MUSCLE PROTEIN SYNTHESIS

新生儿肌肉蛋白合成的激素调节

基本信息

批准号：
2910892
负责人：
TERESA A DAVIS
金额：
$ 23.57万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-20 至 2003-06-30
项目状态：
已结题

项目摘要

The long-term objectives are to identify the mechanisms by which hormones and nutrients interact to regulate the high rate of skeletal muscle protein deposition in the neonate, and to determine how these mechanisms are altered by sepsis. The goal is to identify new strategies to optimize nutrient utilization for growth in growth-retarded and septic infants. Rapid accretion of skeletal muscle mass is a particularly important characteristic of neonatal growth. Previous work has shown that the feeding-induced stimulation of muscle protein synthesis in normal neonates involves regulation by both insulin and amino acids. However, because of the exquisite sensitivity of muscle protein synthesis to insulin and amino acids in the normal neonate, it could not be discerned whether both anabolic agents interact to regulate muscle protein synthesis. Sepsis contributes substantially to the morbidity and mortality of neonates, a population with limited muscle protein stores. Hormonal changes and substrate deficiency likely contribute to the muscle wasting that occurs with sepsis. The hypotheses are: 1) amino acids enhance the sensitivity of muscle protein synthesis to insulin levels in neonates, 2) the interaction of amino acids and insulin reflects their independent effects on the activity of eukaryotic initiation factors (eIFs) and signaling kinases, and 3) sepsis inhibits muscle protein synthesis in neonates via an interaction of tumor necrosis factor alpha (TNFalpha) with insulin-mediated protein synthesis, an effect that can be circumvented by amino acids. The following aims are proposed to address these hypotheses: In Aim 1, the dose response of muscle protein synthesis to insulin and the effect of amino acids on this response will be determined in normal neonates. To achieve this, studies will be performed in 7-d-old pigs using direct kinetic measurement of muscle protein synthesis and refinements of a novel hormone-substrate clamp technique. In Aim 2, the effects of insulin and amino acids on the activity of key eIFs will be determined. To achieve this, muscles from the experiments in Aim 1 will be used to determine the quantitative relationships among protein synthesis rates, the activity of the eIFs that are involved in the binding of Met-tRNA and mRNA to the 40S ribosomal subunit, and the activation of signaling kinases. This will identify the specific translational processes regulated by insulin and amino acids in vivo. In Aim 3, the response of muscle protein synthesis to insulin following administration of endotoxin, TNFalpha, anti-cytokine therapy, and enhanced amino acid supply will be determined. These studies will identify the role of hormones, cytokines, and nutrients in the sepsis-induced muscle wasting in neonates. The practical efficacy of amino acid administration to circumvent the sepsis-induced insulin resistance of muscle protein synthesis will be identified.

长期目标是确定激素和营养物质相互作用以调节新生儿骨骼肌蛋白质沉积的高比率的机制，并确定这些机制如何因脓毒症而改变。目标是确定新的策略，以优化营养利用，以促进生长迟缓和败血症婴儿的生长。骨骼肌块的快速增长是新生儿生长的一个特别重要的特征。先前的工作表明，喂养诱导的对正常新生儿肌肉蛋白质合成的刺激涉及胰岛素和氨基酸的调节。然而，由于正常新生儿肌肉蛋白质合成对胰岛素和氨基酸的高度敏感性，尚不能区分这两种合成代谢物质是否相互作用来调节肌肉蛋白质合成。败血症在很大程度上增加了新生儿的发病率和死亡率，这是一个肌肉蛋白储备有限的人群。荷尔蒙变化和底物缺乏可能是败血症时肌肉萎缩的原因。这些假说是：1)氨基酸增加新生儿肌肉蛋白质合成对胰岛素水平的敏感性；2)氨基酸与胰岛素的相互作用反映了它们对真核细胞起始因子(EIF)和信号转导酶活性的独立影响；3)脓毒症通过肿瘤坏死因子α(TNFpha)与胰岛素介导的蛋白质合成的相互作用抑制新生儿肌肉蛋白质合成，这种作用可被氨基酸所规避。提出以下目标来解决这些假说：在目标1中，将确定正常新生儿肌肉蛋白质合成对胰岛素的剂量反应以及氨基酸对这一反应的影响。为了实现这一点，将在7日龄的猪身上进行研究，使用肌肉蛋白质合成的直接动力学测量和一种新的激素底物钳制技术的改进。在目标2中，将确定胰岛素和氨基酸对关键的EIF活性的影响。为了实现这一点，目标1中实验中的肌肉将被用来确定蛋白质合成速率、参与Met-tRNA和mRNA与40S核糖体亚基结合的EIF的活性以及信号转导酶激活之间的定量关系。这将确定体内受胰岛素和氨基酸调控的特定翻译过程。在目标3中，将确定内毒素、肿瘤坏死因子α、抗细胞因子治疗和增加氨基酸供应后肌肉蛋白质合成对胰岛素的反应。这些研究将确定激素、细胞因子和营养物质在败血症引起的新生儿肌肉萎缩中的作用。给予氨基酸来规避脓毒症诱导的肌肉蛋白质合成的胰岛素抵抗的实际效果将被确定。