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: 8295709
• 负责人: S. Russ Price
• 金额: $ 33.84万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295709
• 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; 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. PUBLIC HEALTH RELEVANCE: Protein-energy wasting (PEW) is a consequence of chronic kidney disease that causes weakness and fatigue, thus reducing patients' quality of life. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) is an important regulatory protein that helps to preserve lean body mass. This project will investigate the cell signals that regulate the level of PGC-1a. An exercise intervention that may maintain the level in PGC- 1a and ameliorate wasting will be tested.

描述(由申请人提供)：蛋白质-能量浪费导致慢性肾脏疾病(CKD)患者经常出现的虚弱和疲劳。尽管在理解导致瘦体重和蛋白质储备损失的机制方面取得了重大进展，但开发药物干预以减少消耗的尝试一直未获成功。相比之下，运动可以减少CKD中的蛋白质分解并保持瘦体重，尽管其影响是如何实现的仍然知之甚少。我们和其他人已经报道了转录共激活物过氧化物酶体增殖物激活受体的水平 在慢性肾脏病和其他诱发恶病质的情况下，γ-辅活化子1-α(PGC-1a)减少。这是值得注意的，因为PGC-1a在正常肌肉中的表达通过运动而增加，而转基因PGC-1a的过度表达可以保护肌肉免受损失。PGC-1a是一种整合能量和蛋白质代谢的关键“主调节因子”。它通过促进线粒体的生物发生和减弱FOXO等重要转录因子的活性来发挥作用，FOXO可以上调蛋白分解系统的基因。了解运动如何减少慢性肾脏病的消耗将提高我们治疗患者疲劳和虚弱的能力。为了实现这一目标，我们必须首先了解在CKD诱导的消耗过程中PGC1a调节失调的生化基础。该项目将验证一种假设，即CKD和糖皮质激素相关的损耗过程中PGC-1a表达的减少是通过一个或多个受钙激活的丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶(CN)调节的信号异常造成的。我们将研究肌细胞增强因子2(MEF2)/活化T细胞胞浆核因子(NFATc)途径，因为这两种转录因子都是调节肌肉细胞中PGC-1a转录的CN底物。需要研究的第三个途径是调节CREB 1转导蛋白(TORC1)/环磷酸腺苷反应元件结合蛋白(CREB)途径。TORC1是一种CN激活的CREB转录共激活因子，是PGC-1a表达所必需的。我们的初步证据表明，在恶病质期间，TORC1功能受损。一旦PGC-1a失调的机制被确定，我们将测试运动是否改善了CKD小鼠的CN信号，从而导致PGC-1a表达增加，蛋白质降解减少，力量增强。我们研究的长期目标是改善CKD患者的治疗和康复，可能是通过开发新的运动模拟疗法。鉴于消瘦综合征在一系列令人衰弱的疾病(如癌症、糖尿病、心脏病)中的相似之处，我们的发现可能广泛适用于许多患者。 与公共健康相关：蛋白质能量浪费(PEW)是慢性肾脏疾病的结果，会导致虚弱和疲劳，从而降低患者的生活质量。PGC-1a是一种重要的调节蛋白，有助于维持瘦体重。该项目将研究调节PGC-1a水平的细胞信号。将进行一项运动干预，以维持PGC-1a的水平，并改善消瘦。