Mentored Patient-Oriented Research Career Development Aw

描述（改编自申请人的摘要）：许多疾病状态， 包括糖皮质激素过量和甲状腺功能亢进， 加速蛋白质分解，导致慢性肌肉萎缩， 发病率和死亡率。 确切的细胞机制仍然存在 难以捉摸。 其中一个可能的机制是糖皮质激素-或甲状腺激素 骨骼肌中蛋白合成诱导的抵抗。 胰岛素、支链氨基酸（BCAA）、平衡氨基酸（AA）混合物 和胰岛素样生长因子1（IGF-1）都被证明可以延缓 蛋白水解和/或增强蛋白质合成。 研究人员建议 研究肌肉对这四种合成代谢剂的反应， 急性和慢性糖皮质激素和甲状腺激素过量。 这些研究将 在有或没有地塞米松的健康人类受试者中进行，或 三碘甲腺原氨酸摄入与库欣综合征患者或 甲状腺功能亢进症通过检查：a）前臂肌肉蛋白质周转; B） 参与信号传导的两个关键调节蛋白的磷酸化状态 mRNA翻译（PHAS-I和p70 S6激酶）;和c）活性、蛋白质 泛素-蛋白酶体中几种组分的含量和表达 蛋白水解途径。 研究结果应有助于确定 与糖皮质激素或甲状腺激素相关的加速蛋白水解 过度 他们将定义：l）胰岛素、BCAA、AA混合物和 IGF-1通过刺激两个关键蛋白的磷酸化来增加蛋白质合成 参与蛋白质翻译起始的调节蛋白（PHAS-I和 2）胰岛素、支链氨基酸、AA混合物和IGF-1是否能延缓 通过阻断泛素-蛋白酶体蛋白水解途径进行蛋白水解;以及 3)无论是糖皮质激素还是甲状腺激素过量都会激活泛素， 蛋白酶体途径和拮抗胰岛素，支链氨基酸，AA的合成代谢作用 混合物和IGF-1。 通过了解细胞机制， 加速肌肉catenation和行动的四个合成代谢剂， 肌肉，这可能是可能的，以纠正蛋白质浪费和减少 相关的发病率和死亡率。

DESCRIPTION (Adapted from the applicant's abstract): Many disease states, including glucocorticoid excess and hyperthyroidism, are associated with accelerated protein catabolism, causing chronic muscle wasting and increasing morbidity and mortality. The exact cellular mechanisms responsible remain elusive. One of the possible mechanisms is glucocorticoid- or thyroid hormone-induced resistance to the anabolic agents in skeletal muscle. Insulin, branched chain amino acids (BCAA), balanced amino acid (AA) mixtures and insulin-like growth factor 1 (IGF-1) all have been demonstrated to retard proteolysis and/or enhance protein synthesis. The investigators propose to study the muscle's response to these four anabolic agents in the setting of acute and chronic glucocorticoid and thyroid hormone excess. The studies will be conducted in healthy human subjects with or without dexamethasone or triiodothyronine ingestion and patients with Cushing's syndrome or hyperthyroidism by examining: a) protein turnover in forearm muscle; b) the phosphorylation status of two key regulatory proteins involved in signaling mRNA translation (PHAS-I and p70 S6 kinase); and c) the activity, protein content and expression of several components in the ubiquitin-proteasome proteolytic pathway. The results should help to define the mechanisms of accelerated proteolysis associated with glucocorticoid or thyroid hormone excess. They will define: l) whether insulin, BCAA, AA mixtures and IGF-1 increase protein synthesis by stimulating phosphorylation of two key regulatory proteins involved in the protein translation initiation (PHAS-I and p70 S6 kinase); 2) whether insulin, BCAA, AA mixtures and IGF-1 retard proteolysis via blocking the ubiquitin-proteasome proteolytic pathway; and 3) whether glucocorticoid or thyroid hormone excess activates the ubiquitin- proteasome pathway and antagonizes the anabolic actions of insulin, BCAA, AA mixtures and IGF-1. By understanding the cellular mechanisms underlying the accelerated muscle catabolism and the actions of four anabolic agents in muscle, it may be possible to correct the protein wasting and to decrease the associated morbidity and mortality.