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Altered nucleus-cytoskeleton coupling in dystrophic muscle

营养不良性肌肉中核-细胞骨架耦合的改变

基本信息

批准号：
10615087
负责人：
Shama Rajan Iyer
金额：
$ 8.33万
依托单位：
MARYMOUNT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615087
关键词：
Ablation Acceleration Actins Adult Automobile Driving Biochemistry Biological Assay Cell Nucleus Cell physiology Cells Cellular Structures Complex Coupling Cytoplasm Cytoskeleton Development Disease Disease Progression Duchenne muscular dystrophy Dystrophin Elements Emery-Dreifuss Muscular Dystrophy Engineering Environment Fluorescence Resonance Energy Transfer Fluorescent in Situ Hybridization Functional disorder Gene Expression Genetic Genetic Models Genetic Transcription Goals Growth Health Impairment Injury Instruction Intermediate Filaments Isometric Exercise Knowledge Lasers Lead Link MAPK3 gene Maintenance Manuals Maryland Measurement Measures Mechanical Stress Mechanics Mentorship Microscopy Microtubule Alteration Microtubules Modeling Molecular Biology Movement Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Muscular Dystrophies Musculoskeletal Nuclear Organelles Pathology Pathway interactions Patients Physical therapy Physiology Positioning Attribute Post-Translational Protein Processing Predisposition Process Proliferating Proteins Publishing RNA Railroads Regulator Genes Rest Role Signal Pathway Skeletal Muscle Spatial Distribution Stress Stretching Structure Testing Therapeutic Effect Universities Wasting Syndrome Work experience improved insight mechanical force mechanical signal mechanotransduction medical schools micro-dystrophin mini-dystrophin mouse model multidisciplinary new therapeutic target novel therapeutic intervention nucleocytoplasmic transport pharmacologic protein complex research faculty response sensor skeletal muscle wasting skills tenure track tool transmission process

项目摘要

Project Summary: Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is characterized by progressive wasting of skeletal muscles and marked susceptibility to damage. Several associated processes could underlie the pathology. The nucleus, a regulator of gene expression and a mechanotransduction hub, has increased movement in mdx (murine model of DMD) muscle. Microtubules (MTs) serve as the “railroad tracks” for cellular organelle transport, including the nucleus. The nucleus is connected to MTs and the rest of the cytoskeleton through the LINC (linkers of nucleus and cytoskeleton) complex. Both, MT organization and LINC complex expression are altered in dystrophic muscle. I will test the hypothesis that nuclear instability, due to disease-driven MT network and LINC complex alterations, results in improper myonuclear domain maintenance (with hypermobile and improperly positioned nuclei), and impaired nuclear mechanotransduction, further driving muscle weakness and susceptibility to injury in dystrophic muscle. In WT and mdx muscle I will measure: 1) nuclear spatial distribution & nuclear movement using time-lapse microscopy 2) myonuclear domain maintenance by measuring RNA spatial distribution of cargoed proteins using fluorescence in-situ hybridization; and nuclear movement & global transcriptional activity following gaps in myonuclear domain using laser ablation 3) nuclear localization of Yes- associated protein (a nuclear relay of mechanical signaling), ERK 1/2 (a key marker of muscle growth) and FRET based nuclear strain sensors, as end points of nuclear mechanotransduction, following passive stretch, isometric and eccentric contractions 4) myonuclear domain maintenance and nuclear mechanotransduction, following blockage of stretch activated channels to block sarcolemmal signaling pathways 5) the above parameters using established genetic/pharmacologic manipulations to the MT network & the LINC complex, and following mini- and micro-dystrophins that have previously shown to either fully or partially rescue MT network and susceptibility to injury Successful completion of this proposal will allow for the development of new avenues to improve musculoskeletal health for patients with DMD, and potentially other dystrophies. This proposal takes place in a multi-disciplinary environment at University of Maryland School of Medicine, with support from experts in physical therapy, physiology, molecular biology, biochemistry, and engineering, such that I can gain skills in cellular and muscle mechanics to move towards an independent, tenure-track research faculty position.

项目总结: