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.

项目摘要： Duchenne肌肉营养不良（DMD）是最常见和严重的肌肉营养不良的形式，是其特征是逐渐浪费骨骼肌肉和明显的损伤易感性。一些相关的过程可能是病理的基础。核，基因表达和A的调节剂机械转导枢纽的MDX（DMD鼠模型）肌肉的运动增加。微管（MT）充当细胞器细胞器转运的“铁轨”，包括核。核是连接到MTS和其余的细胞骨架（通过细胞核和细胞骨架的接头）连接复杂的。 MT组织和LINC复合体表达都在营养不良的肌肉中改变。我将测试假设核不稳定是由于疾病驱动的MT网络和林的复杂变化，导致肌核域维持受损（超动且位置不当），并受损核机械转导，进一步推动肌肉无力和营养不良的损伤易感性肌肉。在WT和MDX肌肉中，我将测量： 1）使用延时显微镜的核空间分布和核运动 2）通过使用使用货物蛋白的RNA空间分布来维护肌核域荧光原位杂交；以及差距之后的核运动和全球转录活动使用激光消融的肌能结构域 3）核定蛋白的核定位（机械信号传导的核继电器），ERK 1/2（钥匙肌肉生长的标记）和基于FRET的核应变传感器，作为核的终点机械转传，后期延伸后，等距和偏心收缩 4）在拉伸阻塞后，肌核域维护和核机械转导激活的通道阻止肌膜信号通路 5）上述参数，使用已建立的遗传/药理操纵到MT网络和 Linc Complex综合体，以及以前已显示为完全或部分显示的微型和微肌营养物救援MT网络和受伤的易感性成功完成该提案将允许开发新途径来改善 DMD患者和其他营养不良患者的肌肉骨骼健康。该提议发生在马里兰大学医学院的多学科环境，在专家的支持下物理疗法，生理学，分子生物学，生物化学和工程学，以便我可以获得技能细胞和肌肉力学朝着独立的终身轨道研究教师迈进。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Muscle phenotype of a rat model of Duchenne muscular dystrophy.

DOI：
10.1002/mus.27061
发表时间：
2020-12
期刊：
Muscle & nerve
影响因子：
3.4
作者：
Iyer SR;Xu S;Shah SB;Lovering RM
通讯作者：
Lovering RM

The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle.

DOI：
10.3389/fphys.2021.724010
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Iyer SR;Folker ES;Lovering RM
通讯作者：
Lovering RM

Alterations of neuromuscular junctions in Duchenne muscular dystrophy.

DOI：
10.1016/j.neulet.2020.135304
发表时间：
2020-10-15
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Lovering RM;Iyer SR;Edwards B;Davies KE
通讯作者：
Davies KE

Abnormalities in Brain and Muscle Microstructure and Neurochemistry of the DMD Rat Measured by in vivo Diffusion Tensor Imaging and High Resolution Localized 1H MRS.

通过体内扩散张量成像和高分辨率局部 1H MRS 测量 DMD 大鼠的大脑和肌肉微观结构和神经化学异常。

DOI：
10.3389/fnins.2020.00739
发表时间：
2020
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Xu,Su;Tang,Shiyu;Li,Xin;Iyer,ShamaR;Lovering,RichardM
通讯作者：
Lovering,RichardM

Inhibition of YAP signaling improves recovery in injured skeletal muscle.

抑制 YAP 信号可改善受损骨骼肌的恢复。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Iyer,ShamaR;Shah,SameerB;Ward,ChristopherW;Stains,JosephP;Folker,EricS;Lovering,RichardM
通讯作者：
Lovering,RichardM