The Role of PGC-1aplha in the Pathogenesis of Myotonic Dystrophy Type 1

PGC-1aplha 在 1 型强直性肌营养不良发病机制中的作用

• 批准号: 8734491
• 负责人: Xiang Fang
• 金额: $ 19万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734491
• 关键词: 19q13.3; 3' Untranslated Regions; 5' -AMP-activated protein kinase; Address; Atrophic; Biogenesis; CREB1 gene; Cell Respiration; Cells; Chromosomes; Chronic; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Degenerative Disorder; Development; Ectopic Expression; Enzymes; Family; Fiber; Gene Targeting; Genes; Genetic Transcription; Glucose; Goals; Homeostasis; Hyperglycemia; Inherited; Insulin Resistance; Intervention; Lead; Length; Maintenance; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Muscle; Muscle Weakness; Mutation; Myoblasts; Myotonic Dystrophy; NADPH Oxidase; Neuromuscular Junction; Nucleotides; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Process; Protein-Serine-Threonine Kinases; Proteins; RNA; Reactive Oxygen Species; Regulation; Respiration; Role; Severities; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; Transcript; Transducers; Translating; ataxia telangiectasia mutated protein; fatty acid metabolism; insight; member; mutant; promoter; public health relevance; receptor; research study; sensor; therapy development; transcription factor; wasting

DESCRIPTION (provided by applicant): Skeletal muscle defects in myotonic dystrophy type 1 (DM1) are characterized by progressive muscle weakness and wasting, impaired mitochondrial (Mt) respiration, hyperglycemia and insulin resistance, diminished metabolic capacity and elevated oxidative stress. Highly complex and degenerative phenotypes in DM1 manifest as the result of massive expansion of a CTG tri-nucleotide repeat in the 3' translated region of DMPK gene in chromosome 19q13.3. The mechanism by which expanded CTG repeats impair Mt function and metabolic regulations in DM1 is unknown. PGC-1 is a transcription co- activator that regulates transcription of genes that regulate Mt respiration, metabolism of fatty acid and glucose and reactive oxygen species (ROS), and activity of the neuromuscular junction (NMJ). In this project our goal is to determine the extent to which diminished PGC-1 activity contributes to muscle pathogenesis in DM1: 1) aim 1 will assess expressions of PGC-1 target genes regulating Mt respiration, and function of neuromuscular junction (NMJ) in DM1 skeletal muscle. The expected outcome will establish the role of decreased PGC-1 and its target genes in skeletal muscle pathology in DM1; 2) aim 2 will establish the mechanism/s by which mutant CUG RNA disrupts intracellular redox homeostasis in DM1. These experiments will establish the mechanism by which PGC-1 target genes catalyzing metabolism of endogenous ROS are disrupted in DM1, and determine whether the activity of the ROS producing enzyme NADPH oxidase is up- regulated in DM1 myoblasts and C2C12 cells expressing mutant CUG repeats; and 3) aim 3 will explore the mechanism by which expanded CUG repeats cause a redox-dependent activation of Ataxia Telangiectasia- Mutated (ATM) kinase, phosphorylates and alters AMPK activity in DM1. We will also test whether activated AMPK modulates phosphorylation of TORC2 (transducer of regulated CREB activity), and regulates CREB activity and CREB-mediated transcription of PGC-1 in DM1. We will also test whether expanded CUG repeats modulate TORC2-mediated CREB activity and transcription of PGC-1 in DM1. The proposed study will provide insight into the mechanism by which mutant CUG RNA disrupts PGC-1 activity and impair Mt function, and might lead to the development of intervention through modulating PGC-1 signaling in DM1.

描述（由申请人提供）：强直性肌营养不良1型（DM 1）中的骨骼肌缺陷的特征在于进行性肌无力和消瘦、线粒体（Mt）呼吸受损、高血糖症和胰岛素抵抗、代谢能力降低和氧化应激升高。DM 1中高度复杂和退化的表型表现为染色体19q13.3中DMPK基因3'翻译区中CTG三核苷酸重复序列的大量扩增的结果。扩展CTG重复损害MT功能和DM 1代谢调节的机制尚不清楚。PGC-1是调节基因转录的转录共激活因子，所述基因调节Mt呼吸、脂肪酸和葡萄糖以及活性氧物质（ROS）的代谢以及神经肌肉接头（NMJ）的活性。在这个项目中，我们的目标是确定减少的PGC-1活性在DM 1中对肌肉发病机制的贡献程度：1）目的1将评估调节Mt呼吸的PGC-1靶基因的表达，以及DM 1骨骼肌中神经肌肉接头（NMJ）的功能。预期的结果将建立减少的PGC-1及其靶基因在DM 1中骨骼肌病理学中的作用; 2）目的2将建立突变CUG RNA破坏DM 1中细胞内氧化还原稳态的机制。这些实验将建立催化内源性ROS代谢的PGC-1靶基因在DM 1中被破坏的机制，并确定ROS产生酶NADPH氧化酶的活性在表达突变CUG重复的DM 1成肌细胞和C2 C12细胞中是否被上调;和3）目的3将探索扩展的CUG重复序列引起共济失调毛细血管扩张突变（ATM）激酶的氧化还原依赖性激活的机制，磷酸化并改变DM 1中AMPK活性。我们还将测试激活的AMPK是否调节TORC 2（调节CREB活性的转导子）的磷酸化，并调节CREB活性和CREB介导的DM 1中PGC-1的转录。我们还将测试扩展的CUG重复序列是否调节TORC 2介导的CREB活性和DM 1中PGC-1的转录。这项研究将深入了解突变体CUG RNA破坏PGC-1活性并损害Mt功能的机制，并可能通过调节DM 1中的PGC-1信号传导来进行干预。