Calcineurin signaling, PGC-1 alpha and protein-energy wasting in kidney disease

肾脏疾病中的钙调磷酸酶信号传导、PGC-1 α 和蛋白质能量浪费

• 批准号: 8817283
• 负责人: S. Russ Price
• 金额: $ 33.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817283
• 关键词: Animals; Atrophic; Attenuated; Biochemical; Biogenesis; CREB1 gene; Cachexia; Calcineurin; Calcium; Chronic; Chronic Kidney Failure; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Dexamethasone; Diabetes Mellitus; Disease; Down-Regulation; Energy Metabolism; Exercise; Fasting; Fatigue; Genes; Genetic Transcription; Glucocorticoids; Goals; Growth; Heart Diseases; Inflammation; Intervention; Kidney Diseases; Link; Malignant Neoplasms; Malnutrition; Mediating; Messenger RNA; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Nuclear; PPAR gamma; Pathway interactions; Patients; Pharmacologic Substance; Phosphorylation; Protein Serine/Threonine Phosphatase; Proteins; Proteolysis; Quality of life; Rattus; Rehabilitation therapy; Reporting; Research; Rodent; Signal Pathway; Signal Transduction; System; Testing; Toxin; Transcription Coactivator; Transducers; Transgenic Mice; Transgenic Organisms; Wasting Syndrome; base; gene induction; genetic regulatory protein; improved; lean body mass; mimetics; muscle form; muscle strength; myocyte-specific enhancer-binding factor 2; nuclear factors of activated T-cells; overexpression; protein degradation; protein function; protein metabolism; receptor; response; transcription factor; wasting

DESCRIPTION (provided by applicant): Protein-energy wasting contributes to the weakness and fatigue that is frequently seen in patients with chronic kidney disease (CKD). Despite significant advances in understanding the mechanisms causing the loss of lean body mass and protein reserves, attempts to develop pharmaceutical interventions to attenuate wasting have been unsuccessful. In contrast, exercise can reduce proteolysis and preserve lean body mass in CKD although how its effects are achieved remains poorly understood. We and others have reported that the level of the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) is decreased during CKD and other cachexia-inducing conditions. This is notable because PGC-1a expression in normal muscle is increased by exercise and transgenic overexpression of PGC-1a protects against muscle loss. PGC-1a is a critical "master regulator" that integrates energy and protein metabolism. It functions by promoting mitochondrial biogenesis and attenuating the activity of important transcription factors like FOXO which upregulate proteolytic system genes. Understanding how exercise decreases wasting in CKD will improve our ability to treat fatigue and weakness in patients. To accomplish this goal, we must first understand the biochemical basis for dysregulation of PGC1a during CKD-induced wasting. This project will test the hypothesis that the reduction in PGC-1a expression during CKD and glucocorticoid-related wasting results from abnormal signaling through one or more pathways that are regulated by calcineurin (Cn), a calcium-activated serine/threonine phosphatase. We will examine the myocyte enhancer factor 2 (MEF2)/cytoplasmic nuclear factor of activated T cells (NFATc) pathways because both transcription factors are Cn substrates that regulate PGC-1a transcription in muscle cells. The third pathway to be studied is the Transducer of Regulated CREB 1 (TORC1)/ cyclic AMP-responsive element-binding protein (CREB) pathway. TORC1 is a Cn-activated transcription coactivator of CREB that is required for PGC-1a expression. Our preliminary evidence suggests that TORC1 function is impaired during cachexia. Once the mechanisms of PGC-1a dysregulation are characterized, we will test whether exercise improves Cn signaling in CKD mice, thus leading to increased expression or PGC-1a, decreased protein degradation, and improvement in strength. The long-term goal of our research is to improve the treatment and rehabilitation of CKD patients, perhaps through the development of new exercise mimetic therapies. Given the similarities of the wasting syndromes in a broad range of debilitating diseases (e.g., cancer, diabetes, heart disease), our findings may be widely applicable to many patients.

描述（由申请人提供）：蛋白质能量浪费会导致慢性肾脏疾病（CKD）经常看到的弱点和疲劳。尽管在理解导致瘦体重和蛋白质储量损失的机制方面取得了重大进展，但尝试开发药物干预措施以减轻浪费的尝试并未成功。相比之下，运动可以减少蛋白水解并保留CKD中的瘦体重，尽管如何实现其效果仍然很少了解。我们和其他人报告说，转录共激活剂过氧化物酶体增殖物激活受体的水平 在CKD和其他诱导缓存条件下，伽马共激活因子1-α（PGC-1A）降低。这是值得注意的，因为通过运动和PGC-1A的转基因过表达增加了正常肌肉中的PGC-1A表达可防止肌肉损失。 PGC-1A是一个关键的“主要调节剂”，它整合了能量和蛋白质代谢。它通过促进线粒体生物发生并衰减重要转录因子的活性（例如FoxO）上调蛋白水解系统基因的活性来发挥作用。了解CKD中的运动如何减少将提高我们治疗患者疲劳和无力的能力。为了实现这一目标，我们必须首先了解CKD诱导的浪费期间PGC1A失调的生化基础。该项目将检验以下假设：CKD期间PGC-1A表达的降低和与糖皮质激素相关的浪费在异常信号传导中通过一种或多种途径受到钙调神经磷酸酶（CN）的调节，钙激活的丝氨酸/三氨酸磷酸酶。我们将检查激活T细胞（NFATC）途径的心肌细胞增强因子2（MEF2）/细胞质核因子，因为两个转录因子都是调节肌肉细胞中PGC-1A转录的CN底物。要研究的第三个途径是调节的CREB ​​1（TORC1）/环状AMP响应元件结合蛋白（CREB）途径的传感器。 TORC1是PGC-1A表达所需的CN激活的CREB的转录共激活因子。我们的初步证据表明，在恶病质期间，TORC1功能受损。一旦表征了PGC-1A失调的机制，我们将测试运动是否会改善CKD小鼠的CN信号传导，从而导致表达增加或PGC-1A，蛋白质降低降低和强度改善。我们研究的长期目标是通过开发新运动模拟疗法来改善CKD患者的治疗和康复。鉴于浪费综合症的相似性在广泛的衰弱疾病（例如癌症，糖尿病，心脏病）中，我们的发现可能广泛适用于许多患者。