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.

项目概要：杜氏肌营养不良症 (DMD) 是最常见和最严重的肌营养不良症，其特征是骨骼肌进行性萎缩并且明显容易受到损伤。相关的过程可能是病理学的基础。机械转导中心，增加了 mdx（DMD 小鼠模型）肌肉的运动。（MT）充当细胞器运输的“铁路轨道”，包括细胞核。通过 LINC（细胞核和细胞骨架的连接器）连接到 MT 和细胞骨架的其余部分 MT 组织和 LINC 复合体的表达在营养不良的肌肉中都发生了改变。假设由于疾病驱动的 MT 网络和 LINC 复合体改变导致核不稳定性，导致肌核域维护不当（细胞核过度活动且定位不当）和受损核机械转导，进一步导致营养不良者肌肉无力和易受伤在 WT 和 mdx 肌肉中，我将测量： 1) 使用延时显微镜观察核空间分布和核运动 2) 通过测量负载蛋白的 RNA 空间分布来维持肌核结构域荧光原位杂交；以及核运动和全局转录活性使用激光消融的肌核域 3) Yes相关蛋白的核定位（机械信号的核中继），ERK 1/2（关键肌肉生长的标记）和基于 FRET 的核应变传感器，作为核的终点被动拉伸、等长收缩和离心收缩后的机械传导 4) 拉伸阻断后肌核域的维持和核力转导激活通道以阻断肌膜信号通路 5) 上述参数使用已建立的遗传/药理学操作对 MT 网络和 LINC 复合体，以及之前已证明完全或部分发挥作用的微型和微型肌营养不良蛋白救援MT网络和受伤易感性该提案的成功完成将有助于开发新的改进途径 DMD 和其他潜在营养不良患者的肌肉骨骼健康。马里兰大学医学院的多学科环境，并得到了专家的支持物理治疗、生理学、分子生物学、生物化学和工程学，这样我就可以获得以下方面的技能细胞和肌肉力学向独立的终身教授研究职位迈进。

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）

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：
发表时间：
2020
期刊：
影响因子：
0
作者：
Xu, Su;Tang, Shiyu;Li, Xin;Iyer, Shama R;Lovering, Richard M
通讯作者：
Lovering, Richard M

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：
2022-05
期刊：
影响因子：
0
作者：
Iyer, Shama R;Shah, Sameer B;Ward, Christopher W;Stains, Joseph P;Folker, Eric S;Lovering, Richard M
通讯作者：
Lovering, Richard M

The roles of carnosine in aging of skeletal muscle and in neuromuscular diseases.

肌肽在骨骼肌衰老和神经肌肉疾病中的作用。

DOI：
10.4161/cc.7.16.6440
发表时间：
2000-07-01
期刊：
Biochemistry
影响因子：
2.9
作者：
Stuerenburg Hj
通讯作者：
Stuerenburg Hj

The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle.

核骨架：骨骼肌机械转导的十字路口。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Iyer, Shama R;Folker, Eric S;Lovering, Richard M
通讯作者：
Lovering, Richard M

Exosomes Isolated From Platelet-Rich Plasma and Mesenchymal Stem Cells Promote Recovery of Function After Muscle Injury.

从富含血小板的血浆和间充质干细胞中分离出的外泌体可促进肌肉损伤后的功能恢复。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Iyer, Shama R;Scheiber, Amanda L;Yarowsky, Paul;Henn 3rd, R Frank;Otsuru, Satoru;Lovering, Richard M
通讯作者：
Lovering, Richard M