MKP5 in Dystrophic Muscle Disease

MKP5 在营养不良性肌肉疾病中的作用

• 批准号: 9003031
• 负责人: Anton M Bennett
• 金额: $ 38.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-02 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003031
• 关键词: Adult; Biology; Cell physiology; Cells; Cellular biology; Cessation of life; Chemicals; Coupling; Data; Development; Disease; Duchenne muscular dystrophy; Dystrophin; Enzymes; Equilibrium; Exhibits; Family; Family member; Foundations; Functional disorder; Genetic; Health; Homeostasis; Investigation; JUN gene; Link; MAPK phosphatase; MAPK8 gene; Maintenance; Metabolic; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Dystrophies; Myopathy; Outcome; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Protein Dephosphorylation; Protein phosphatase; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Specificity; Testing; Treatment Efficacy; Work; base; cell growth; cyclin D3; genetic approach; improved; in vivo; inhibitor/antagonist; insight; male; mouse model; muscle regeneration; myogenesis; novel; novel therapeutics; phosphoproteomics; regenerative; research study; small molecule inhibitor; structural biology; therapeutic target; tissue regeneration

 DESCRIPTION (provided by applicant): The mitogen-activated protein kinases (MAPKs) are inactivated by direct dephosphorylation by a family of enzymes known as MAPK phosphatases (MKPs). The MKPs exert unique physiological outcomes by acting as signaling nodes that integrate multiple MAPK activities. The MAPKs are essential positive regulators of regenerative myogenesis. A complete understanding of how the MAPKs are inactivated during regenerative myogenesis has yet to be achieved. Muscle stem cells are required for regenerative myogenesis and their dysfunction causes degenerative skeletal muscle disease. We have identified MKP5 as an essential MKP that opposes MAPK signaling in skeletal muscle and maintains muscle stem cell quiescence. MKP5 deletion in a mouse model of dystrophic muscle disease ameliorates muscular dystrophy. Hence, MKP5 represents a potential therapeutic target for the treatment of dystrophic muscle disease. The degeneration of skeletal muscle function in congenital dystrophic muscle disease leads to death in young male adults and there is neither a cure nor treatment for this disease. We propose a multi-disciplinary plan encompassing the use of mouse genetics, cell biology, phosphoproteomics, structural biology and chemical biology strategies towards defining MKP5 function in muscle stem cells, skeletal muscle function and a potential therapeutic target for the treatment of degenerative skeletal muscle disease. Aim 1 will define the genetic link between MKP5 and JNK dephosphorylation in regenerative myogenesis. How MKP5 participates in maintaining myofiber homeostasis through control of mitochondrial function will be defined. Aim 2 will employ phosphoproteomic strategies to identify and characterize MKP5-regulated MAPK substrates involved in muscle stem cell function and myofiber integrity. Aim 3, will utilize chemical biology approaches to identify MKP5 small molecule inhibitors. Identified MKP5 inhibitors will be used to provide proof-of- principle for the validity of MKP5 inhibition as a therapeutic target for dystrophic muscle disease. If successful, this work will lay the foundation for new avenues of investigation towards MKP5 as a target for the treatment of degenerative skeletal muscle disease.

 描述（由申请人提供）：丝裂原激活蛋白激酶 (MAPK) 通过被称为 MAPK 磷酸酶 (MKP) 的酶家族直接去磷酸化而失活。MKP 通过充当整合多种 MAPK 活性的信号节点来发挥独特的生理结果。 MAPK 是再生肌发生的重要正调节因子，目前尚未完全了解 MAPK 在再生肌发生过程中如何失活。肌肉干细胞是再生肌生成所必需的，它们的功能障碍会导致退行性骨骼肌疾病，我们已确定 MKP5 是一种重要的 MKP，它会对抗骨骼肌中的 MAPK 信号传导并维持营养不良性肌肉小鼠模型中肌肉干细胞的静止状态。因此，MKP5 代表了治疗先天性骨骼肌功能退化的潜在治疗靶点。营养不良性肌肉疾病会导致年轻男性死亡，并且这种疾病既没有治愈方法也没有治疗方法，我们提出了一个多学科计划，包括使用小鼠遗传学、细胞生物学、磷酸化蛋白质组学、结构生物学和化学生物学策略来定义 MKP5。目标 1 将确定 MKP5 和 JNK 去磷酸化在再生肌生成中的遗传联系。将定义 MKP5 通过控制线粒体功能参与维持肌纤维稳态。目标 2 将采用磷酸蛋白质组学策略来识别和表征参与肌肉干细胞功能和肌纤维完整性的 MKP5 调节的 MAPK 底物。目标 3 将利用化学生物学方法来识别。 MKP5 小分子抑制剂将用于为该研究提供原理验证。 MKP5 抑制作为营养不良性肌肉疾病治疗靶点的有效性如果成功，这项工作将为 MKP5 作为退行性骨骼肌疾病治疗靶点的新研究途径奠定基础。