Mechanisms of protein-energy-wasting in chronic kidney disease

描述（由申请方提供）：肌肉萎缩是慢性肾脏疾病（CKD）的严重并发症，因为它会导致患者的发病率和死亡率。肌肉萎缩主要反映了肌原纤维蛋白的分解增加。大量证据表明，泛素-蛋白酶体系统（UPS）是骨骼肌蛋白质丢失的主要原因。我们已经证明，在CKD小鼠的肌肉中，抑制IGF-1/PI 3激酶/Akt信号通过刺激影响UPS介导的肌肉蛋白水解的E3泛素连接酶（Atrogin-1，MuRf-1）来增强UPS活性。IGF-1/PI 3 K/p-Akt通路的缺陷刺激半胱天冬酶-3活化并导致肌肉萎缩。我们还发现线粒体功能障碍和能量代谢受损会导致肌肉萎缩。在这个拟议的项目中，我计划研究ROCK 1作为与UPS激活和线粒体功能障碍相关的关键分子。该项目得到了初步结果的支持：1）在CKD小鼠的肌肉中，ROCK 1活性增加，这种变化与低水平的p-Akt和增加的线粒体分裂有关; 2）肌肉特异性ROCK 1激活刺激肌肉蛋白水解并导致线粒体功能障碍; 3）在CKD小鼠中，ROCK 1敲除可改善肌肉萎缩。我们假设CKD激活ROCK 1，导致PTEN激活和线粒体分裂，最终导致肌肉萎缩。我们将通过研究以下三个目标来实现这一目标：目标1：确定CKD如何激活ROCK 1，导致PI 3 K/Akt信号转导抑制和肌肉蛋白水解增强。目的2：确定CKD和线粒体功能障碍之间的关联，并探讨ROCK 1如何介导线粒体分裂。目的3：确定ROCK 1和PTEN的药理学抑制是否会逆转CKD引起的肌肉萎缩。 我们提出了一个新的途径，调节肌肉蛋白质和能量代谢的CKD。因为这条途径可以被操纵。我们的研究结果可用于定义CKD中断的细胞生物学反应。研究结果也可能为设计治疗这种可怕的CKD并发症的新疗法迈出初步步伐。.

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. .