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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： -- Duchenne肌营养不良症(DMD)是最常见和最严重的肌营养不良症，以骨骼肌逐渐消瘦和对损伤明显敏感为特征。几个相关的过程可能是病理的基础。细胞核，一个基因表达的调节器和一个机械转导中枢，增加了MDX(DMD小鼠模型)肌肉的运动量。微管 (MT)是包括细胞核在内的细胞器运输的“铁轨”。原子核是通过LINC(细胞核和细胞骨架的连接物)连接到MTS和其余的细胞骨架很复杂。营养不良肌肉中MT组织和LINC复合体的表达均发生改变。我会测试一下假设核不稳定，由于疾病驱动的MT网络和LINC复合体改变，导致肌核结构域维护不当(细胞核过度移动和位置不正确)，并受损核力学转导，进一步驱动营养不良患者的肌肉无力和损伤易感性肌肉。在WT和MDX肌肉中，我将测量： 1)用时间推移显微镜研究原子核的空间分布和运动 2)通过测量蛋白质的RNA空间分布来维持肌核结构域荧光原位杂交；以及核移动和缺口后的全球转录活性激光消融肌核区 3)YES相关蛋白的核定位(机械信号的核传递)，ERK 1/2(一个关键肌肉生长的标志)和基于FRET的核应变传感器，作为核的终点被动拉伸、等长收缩和偏心收缩后的机械转导 4)牵张阻断后肌核结构域的维持和核力学转导激活的通道阻断肌膜信号通路 5)使用已建立的对MT网络的遗传/药物操作的上述参数& LINC复合体，以及以下微型和微肌营养不良蛋白，先前已显示完全或部分 MT救援网络与损伤易感性这项提案的成功完成将有助于开发新的改进途径 DMD患者的肌肉骨骼健康，以及潜在的其他营养不良患者。这项提议发生在一个在马里兰大学医学院的多学科环境下，在理疗、生理学、分子生物学、生物化学和工程学，这样我就可以学到细胞和肌肉力学，走向一个独立的，终身教职的研究教员职位。