Microtubule acetylation is a novel target in Duchenne muscular dystrophy

总结 杜氏肌营养不良症（DMD）的病理与细胞骨架和生化加速有关， 骨骼肌的不断退化和心肌病的发展。微管增殖 增加细胞骨架硬度，其驱动过度机械转导引起活性氧物质 (ROS)和与DMD病理学相关的钙（Ca 2+）信号传导。有证据表明，有针对性地减少MT DMD心脏和骨骼肌中的增殖减少的工作负荷损伤已经引起了人们对 MT机械传导机制、其在DMD中的改变及其作为新型治疗药物的靶向作用 减缓DMD进展的机会。这项建议的重点是乙酰化β-微管蛋白，微管蛋白后， 翻译修饰调节MT的结构和功能。β-微管蛋白的乙酰化反应发生在细胞 应力和调节MT机械特性和细胞机械敏感性。PI的新初步数据 显示MT乙酰化调节横纹肌细胞骨架刚度和机械激活的ROS产生， 肌肉，并确定该PTM在DMD肌肉中升高。综合起来，这些发现为总体 假设MT乙酰化影响细胞骨架刚度，通过Nox 2- 在DMD患者中，MT乙酰化水平的升高可作为一种抗氧化剂。 疾病修饰剂，并且可以靶向治疗益处。独立之路补助金的目标是 建议为PI提供肌肉和心脏功能测量以及分子水平的高级培训。 生物学技术为他的独立研究铺平了道路，同时推动了这些新发现 对横纹肌中MT乙酰化作用的机制理解。

Summary Duchenne muscular dystrophy (DMD) pathology is associated with cytoskeletal and biochemical accelerate the relentless degeneration of skeletal muscle and the development of cardiomyopathy. Microtubule proliferation increases cytoskeletal stiffness which drives the excess mechanotransduction elicited reactive oxygen species (ROS) and calcium (Ca2+) signaling linked to DMD pathology. Evidence that the targeted reduction of MT proliferation reduced workload injury in DMD heart and skeletal muscle has generated great interest in the mechanisms of MT mechanotransduction, its alteration in DMD, and its targeting as a novel therapeutic opportunity to slow DMD progression. The focus of this proposal is acetylation of -tubulin, a tubulin post- translational modification regulates MT structure and function. Acetylation of -tubulin occurs in response to cell stress and modulates the MT mechanical proprieties and cell mechano-sensitivity. The PI’s new preliminary data shows that MT acetylation regulates cytoskeletal stiffness and mechano-activated ROS production in striated muscle and identifies this PTM elevated in DMD muscle. Taken together these findings inform the overarching hypothesis that MT acetylation impacts cytoskeletal stiffness to regulate mechanotransduction through Nox2- ROS and Ca2+ in healthy cardiac and skeletal muscle and that the elevation of MT acetylation in DMD acts as a disease modifier and can be targeted for therapeutic benefit. This goal of this Pathway to Independence Grant proposal is to provide the PI advanced training in muscle and heart function measurements and molecular biology techniques to pave his way to independent research while and advancing these novel discoveries towards a mechanistic understanding of role MT acetylation in striated muscle.