Microtubule acetylation is a novel target in Duchenne muscular dystrophy

微管乙酰化是杜氏肌营养不良症的新靶点

基本信息

批准号：
10212666
负责人：
Humberto Cavalcante Joca
金额：
$ 12.29万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212666
关键词：
Acetylation Acute Antibodies Applications Grants Atomic Force Microscopy Biochemical Calcium Cardiac Myocytes Cardiomyopathies Cells Cellular Stress Confocal Microscopy Cytoskeleton Data Disease Disease Progression Duchenne muscular dystrophy Dystrophin Echocardiography Event Genetic Goals Grant Heart Heart Injuries Heart failure Histone Deacetylase Inhibitor Hour Impairment In Vitro Injury Investigation Knock-out Lead Link Measurement Measures Mechanics Mentorship Microtubules Molecular Biology Techniques Mus Muscle Muscle Cells Muscle Development Muscle Weakness Muscle function Muscular Dystrophies Myocardium NADPH Oxidase Nerve Pathogenicity Pathology Pathway interactions Performance Pharmacology Phase Post-Translational Protein Processing Production Proteins Publishing Reactive Oxygen Species Relaxation Research Resistance Respiratory Failure Role Sensory Signal Transduction Skeletal Muscle Striated Muscles Structure Testing Tissues Training Transferase Transforming Growth Factor beta Tubulin Western Blotting Work Workload acetovanillone alpha Tubulin genetic approach heart function in vivo inhibitor/antagonist insight interest knock-down mdx mouse mechanotransduction muscle degeneration nanoindentation new therapeutic target novel novel therapeutics overexpression oxidation response response to injury skeletal targeted treatment tool tubacin

项目摘要

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.

概括 Duchenne肌肉营养不良（DMD）病理学与细胞骨架和生化加速有关骨骼肌的无情变性和心肌病的发展。微管增殖增加细胞骨架刚度，从而驱动过量的机械转导的过量引起活性氧（ROS）和钙（Ca2+）信号传导与DMD病理相关。有针对性减少MT的证据增殖减少了DMD心脏和骨骼肌的工作量损伤引起了人们对 MT机械转导的机理，其在DMD中的改变及其作为一种新疗法的靶向减慢DMD进展的机会。该提议的重点是actylation，是微管蛋白的乙酰化，这是一种小管蛋白翻译修饰调节MT结构和功能。 微管蛋白的乙酰化是响应细胞的压力并调节MT机械礼节和细胞机理敏感性。 PI的新初步数据表明MT乙酰化调节细胞骨架刚度和机械激活的ROS产生肌肉并识别DMD肌肉中升高的PTM。这些发现汇总了总体 MT乙酰化会影响细胞骨架刚度以通过NOX2-调节机械转导的假设在健康的心脏和骨骼肌中的ROS和Ca2+，DMD中MT乙酰化的升高充当疾病修饰剂，可以针对治疗益处。这项通往独立授予的途径的目标建议是提供肌肉和心脏功能测量和分子的PI高级训练生物学技术可以铺平自己的独立研究的方式，同时推进这些新颖的发现迈向对果肌中乙酰化的作用的机械理解。