Protein Nutrition in Experimental Uremia

实验性尿毒症中的蛋白质营养

• 批准号: 8004337
• 负责人: WILLIAM Evans MITCH
• 金额: $ 10万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-26 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004337
• 关键词: 1-Phosphatidylinositol 3-Kinase; Chronic Kidney Failure; Complex; Degradation Pathway; Down-Regulation; Enzymes; Exhibits; Experimental Models; Glucocorticoids; Goals; Grant; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Kidney Failure; Mediating; Metabolic acidosis; Metabolism; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscular Atrophy; Myofibrils; PTEN gene; Pathway interactions; Physiological; Process; Proteins; Proteolysis; Role; Signal Pathway; Signal Transduction; Structure; System; Testing; Transgenic Mice; Ubiquitin; Uremia; base; caspase-3; combat; in vivo; insulin receptor substrate 1 protein; mortality; multicatalytic endopeptidase complex; muscle form; muscular structure; novel; nutrition; prevent; protein degradation; receptor; response; wasting

Abnormalities in metabolism leading to loss of muscle mass contribute to the morbidity and mortality of kidney failure. Our long-term goal is to identify uremia-induced mechanisms causing muscle loss in order to devise novel therapies to combat this problem. We have identified new processes that cause muscle protein losses: 1) caspase-3 activation is the initial step that breaks down the complex structure of muscle yielding substrates that are degraded by the ubiquitin system. 2) The trigger that accelerated muscle loss is decreased activity of IRS-1 associated phosphatidylinositol 3-kinase activity (IRS-1-PI3K). Decreased IRS-1- PI3K stimulates caspase-3 and the ubiquitin system, including the critical enzyme, atrogin-1/MAFbx. 3) Physiological levels of glucocorticoids (GC) are absolutely required to activate protein degradation pathways. Thus, we propose a "two hit" process: GC and suppressed insulin responses synergistically suppress IRS-1- PI3K activity and initiate muscle proteolysis. We will test the two hit model using experimental models; mice lacking the insulin or IGF-1 receptor in muscle. We will extend our study to uremia using transgenic mice that exhibit activation of the IRS-1-PI3K pathway (e.g., PTEN deletion, Akt or IGF-1). Specifically, we will: 1) test if there is an essential role for both GC and impaired insulin/IGF-1 responses that stimulates muscle proteolysis in mice with deficiency of the insulin or the IGF-1 receptor or both receptors but only in muscle; 2) examine the mechanism for GC- and insulin/IGF-1 deficiency-dependent downregulation of IRS-1-PI3K activity in muscle; and 3) examine how manipulation of PI3K and Akt activities in vivo will change uremia- induced muscle proteolysis using transgenic mice. The significance of our results is that the two-hit model could apply to many conditions because GC and decreased insulin responses are present in many catabolic illnesses,

代谢的异常导致肌肉质量损失有助于 肾衰竭。我们的长期目标是确定尿毒症引起的机制，导致肌肉损失 设计新颖的疗法来解决这个问题。我们已经确定了引起肌肉蛋白的新过程 损失：1）caspase-3激活是打破肌肉屈服的复杂结构的初始步骤 被泛素系统降解的底物。 2）加速肌肉损失的触发因素是 IRS-1相关的磷脂酰肌醇3-激酶活性（IRS-1-PI3K）的活性降低。 IRS-1-降低 PI3K刺激caspase-3和泛素系统，包括临界酶，Atrogin-1/MAFBX。 3） 激活蛋白质降解途径的糖皮质激素（GC）的生理水平是绝对需要的。 因此，我们提出了一个“两个命中”过程：GC和抑制胰岛素反应协同抑制IRS-1-- PI3K活性并启动肌肉蛋白水解。我们将使用实验模型测试两个命中模型。老鼠 缺少肌肉中的胰岛素或IGF-1受体。我们将使用转基因小鼠将研究扩展到尿毒症 表现出IRS-1-PI3K途径的激活（例如PTEN缺失，AKT或IGF-1）。具体来说，我们将：1） 测试GC和胰岛素/IGF-1刺激肌肉的胰岛素/IGF-1反应是否具有重要作用 胰岛素或IGF-1受体或两个受体缺乏的小鼠中的蛋白水解，但仅在肌肉中； 2） 检查IRS-1-PI3K的GC-和胰岛素/IGF-1缺乏依赖性下调的机制 肌肉活动； 3）检查体内对PI3K和AKT活动的操纵将如何改变尿毒症 - 使用转基因小鼠诱导肌肉蛋白水解。我们结果的意义是两击模型 可以适用于许多条件，因为在许多分解代谢中存在GC和胰岛素反应减少 疾病，