Mechanisms of protein-energy-wasting in chronic kidney disease

慢性肾脏病中蛋白质能量浪费的机制

• 批准号: 9057956
• 负责人: Zhaoyong Hu
• 金额: $ 33.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057956
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Atrophic; CASP3 gene; Cells; Chronic Disease; Chronic Kidney Failure; Complication; DNA Sequence Alteration; Defect; Depressed mood; Diabetes Mellitus; Energy Metabolism; Engineering; FBXO32 gene; FRAP1 gene; Feedback; Figs - dietary; Functional disorder; Genetic; Goals; Growth; Homologous Gene; Insulin-Like Growth Factor I; Knockout Mice; Link; Mediating; Mitochondria; Morbidity - disease rate; Mus; Muscle; Muscle Proteins; Muscular Atrophy; Oxidative Stress; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Production; Protein Biosynthesis; Proteins; Proteolysis; Reporting; Signal Transduction; Skeletal Muscle; System; Transgenic Mice; Ubiquitin; design; forkhead protein; mitochondrial dysfunction; mortality; mouse model; multicatalytic endopeptidase complex; novel therapeutics; prevent; protein degradation; protein metabolism; public health relevance; response; rho; skeletal muscle wasting; tensin; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): Muscle wasting is a serious complication of chronic kidney disease (CKD) because it contributes to patient's morbidity and mortality. Muscle wasting mainly reflects increased breakdown of myofibrillar proteins. Compelling evidence has shown that ubiquitin-proteasome system (UPS) is responsible for skeletal muscle protein loss. We have demonstrated that in muscle of CKD mice, depressed IGF-1/PI3 kinase/Akt signaling augments UPS activity via stimulation of the E3 ubiquitin ligases (Atrogin-1, MuRf-1) that affect UPS-mediated muscle proteolysis. Defects in the IGF-1/PI3K/p- Akt pathway stimulate caspase-3 activation and contribute to muscle wasting. We also have discovered that mitochondrial dysfunction and impaired energy metabolism contribute to muscle wasting. In this proposed project, I plan to study ROCK1 as a key molecule linked both to UPS activation and mitochondrial dysfunction. The proposed project is supported by preliminary Results: 1) in muscle of CKD mice, ROCK1 activity is increased and this change is associated with low levels of p-Akt and increased mitochondrial fission; 2) muscle-specific ROCK1 activation stimulates muscle proteolysis and causes mitochondrial dysfunction; and 3) in CKD mice, knockout of ROCK1 ameliorates muscle wasting. We hypothesize that CKD activates ROCK1 leading to both PTEN activation and mitochondria fission, ultimately resulting in muscle wasting. We will accomplish this goal by studying the following three aims Aim 1: To determine how CKD activates ROCK1 leading to depressed PI3K/Akt signaling and enhanced muscle proteolysis. Aim 2: To determine an association between CKD and mitochondrial dysfunction and explore how ROCK1 mediates mitochondrial fission. Aim 3: To determine if pharmacologic inhibition of ROCK1 and PTEN will reverse the muscle wasting caused by CKD. We propose a new pathway that regulates muscle protein and energy metabolism in CKD. Since this pathway can be manipulated pharmacologically. The results of our study might be used to define cell biologic responses that are interrupted by CKD. The results also might yield the initial steps towards designing new therapies for this dreaded complication of CKD. .

描述（由申请人提供）：肌肉浪费是慢性肾脏疾病（CKD）的严重并发症，因为它有助于患者的发病率和死亡率。肌肉浪费主要反映出增加的肌原纤维蛋白分解。令人信服的证据表明，泛素 - 蛋白酶体系统（UPS）负责骨骼肌蛋白质丧失。我们已经证明，在CKD小鼠的肌肉中，IGF-1/PI3激酶/AKT信号抑制，通过刺激E3泛素连接酶（Atrogin-1，MURF-1）来增强UPS活性，从而影响UPS介导的肌肉蛋白水解。 IGF-1/PI3K/P-AKT途径中的缺陷刺激caspase-3激活并有助于肌肉浪费。我们还发现，线粒体功能障碍和能量代谢受损会导致肌肉浪费。在这个拟议的项目中，我计划将Rock1研究为与UPS激活和线粒体功能障碍相关的关键分子。提出的项目得到了初步结果的支持：1）在CKD小鼠的肌肉中，Rock1活性增加，并且这种变化与p-akt水平较低和线粒体裂变有关； 2）肌肉特异性岩石激活刺激肌肉蛋白水解并引起线粒体功能障碍； 3）在CKD小鼠中，Rock1的敲除可以改善肌肉浪费。我们假设CKD激活Rock1，导致PTEN激活和线粒体裂变，最终导致肌肉浪费。我们将通过研究以下三个目标目标1来实现这一目标：确定CKD如何激活Rock1，从而导致PI3K/AKT信号抑制和增强的肌肉蛋白水解。目标2：确定CKD与线粒体功能障碍之间的关联，并探索Rock1如何介导线粒体裂变。目标3：确定岩石1和PTEN的药理抑制是否会逆转由CKD引起的肌肉浪费。 我们提出了一种调节CKD中肌肉蛋白质和能量代谢的新途径。由于该途径可以通过药理学操纵。我们的研究结果可能用于定义被CKD中断的细胞生物学反应。结果还可能产生针对CKD的可怕并发症设计新疗法的初始步骤。 。