MKP5 in Dystrophic Muscle Disease

 描述（由申请方提供）：丝裂原活化蛋白激酶（MAPK）通过MAPK磷酸酶（MKP）家族直接去磷酸化而失活。MKPs通过作为整合多种MAPK活性的信号节点发挥独特的生理结果。MAPK是再生肌发生的重要正调控因子。MAPKs如何在再生肌发生过程中失活的完整理解尚未实现。肌肉干细胞是再生性肌肉发生所必需的，它们的功能障碍导致退行性骨骼肌疾病。我们已经确定MKP5作为一个重要的MKP，反对MAPK信号在骨骼肌和维持肌肉干细胞静止。营养不良性肌肉疾病的小鼠模型中的MKP 5缺失改善肌营养不良症。因此，MKP 5代表了用于治疗营养不良性肌肉疾病的潜在治疗靶标。先天性肌营养不良性疾病中骨骼肌功能的退化导致年轻男性成年人死亡，并且这种疾病既没有治愈也没有治疗。我们提出了一个多学科的计划，包括使用小鼠遗传学，细胞生物学，磷酸蛋白质组学，结构生物学和化学生物学策略，以确定MKP 5在肌肉干细胞，骨骼肌功能和潜在的治疗靶点，用于治疗退行性骨骼肌疾病。目的1将明确再生肌发生中MKP5和JNK去磷酸化之间的遗传联系。MKP5如何通过控制线粒体功能参与维持肌纤维稳态将被定义。目的2将采用磷酸化蛋白质组学的策略，以确定和表征MKP5调控的MAPK底物参与肌肉干细胞功能和肌纤维的完整性。目的3，利用化学生物学方法鉴定MKP 5小分子抑制剂。已鉴定的MKP 5抑制剂将用于为以下研究提供原理证明： MKP 5抑制作为营养不良性肌肉疾病的治疗靶点的有效性。如果成功，这项工作将为研究MKP 5作为治疗退行性骨骼肌疾病的靶点奠定新的基础。

 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.