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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.

总结