Myokine function of MG53 in muscle injury-repair and regeneration

MG53在肌肉损伤修复和再生中的肌因子功能

基本信息

批准号：
9924247
负责人：
Jianjie Ma
金额：
$ 35.27万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924247
关键词：
Acute Address Animal Model Area Biological Biology Biomedical Research Blood Circulation Cell membrane Cell physiology Cellular Structures Cessation of life Chronic Chronic Phase Clinical Research Data Development Fibroblasts Fibrosis Foundations Goals Human Immune response Injury Intervention Ischemia Ischemic Preconditioning Learning Link Longevity Maintenance Membrane Morbidity - disease rate Multicellular Process Mus Muscle Muscle Fibers Muscle function Muscle satellite cell Muscular Dystrophies Myofibroblast Myopathy Natural regeneration Pathway interactions Phase Physiological Play Process Proliferating Property Protein Family Proteins Reagent Recombinants Regenerative Medicine Regulation Research Role Safety Sarcolemma Signal Transduction Site Skeletal Muscle Skeletal muscle injury Stress TRIM Family Testing Therapeutic Transgenic Mice Translating Vesicle Wild Type Mouse cell injury cell regeneration design experimental study extracellular fiber cell gene repair improved injured injury and repair intravenous administration mdx mouse member mortality mouse model muscle degeneration muscle physiology muscle regeneration novel novel therapeutic intervention preconditioning preservation prevent regenerative repaired response satellite cell stem cells tissue regeneration trafficking translational approach

项目摘要

SUMMARY Skeletal muscle injury-repair and regeneration is a multi-cellular process that involves repair of acute injury to the sarcolemma, mobilization of satellite cells to replace the lost-muscle fibers, and control of fibrotic remodeling for maintenance of muscle integrity. In muscular dystrophy, compromised sarcolemma integrity or membrane repair triggers the cascade of muscle degeneration that incurs progressive, severe morbidity and ultimately mortality. Developing therapeutic approaches to improve sarcolemma integrity while facilitating regeneration of injured muscle fibers remain a major challenge in muscle physiology research. This project builds on the discovery of MG53, a member of the TRIM-family protein, as an essential component of the cell membrane repair machinery. MG53 functions in vesicle trafficking and facilitates the nucleation of intracellular vesicles to sites of membrane disruption for repair patch formation. Native MG53 is present in blood circulation, at levels directly correlating with injury or secretory activity of the muscle. Administration of recombinant human MG53 (rhMG53) protein protects muscle fibers and stem cells from injury, and reduces muscle fibrosis in the mdx mouse model. Our research with MG53 over the past few years has established a potential tri-functional role for MG53 in muscle injury-regeneration, as a facilitator to repair acute sarcolemma injury, a contributor to activate satellite cells during the early phase of muscle injury, and a modulator of fibrosis by controlling fibroblast differentiation associated with chronic muscle injury. We envision that targeting the tri-functional role of MG53 will have advantage over the current paradigms for treating muscular dystrophy. In Aim 1, we will determine the pathways that transduce the newly identified myokine function of MG53 into activation of satellite cells in response to acute muscle injury; define the mechanisms that underlie MG53’s function in regulating fibrosis during chronic muscle injury; and test if non-invasive interventions can modulate circulating MG53 levels toward muscle injury-regeneration. If circulating MG53 plays a role in satellite cell activation, we predict that ischemia-preconditioning that releases MG53 without muscle injury, or inducible secretion of MG53 from a transgenic mouse model, will effectively activate satellite cells and muscle regeneration following injury. In Aim 2, we will evaluate the safety and efficacy for sustained elevation of MG53 in circulation to preserve muscle integrity/satellite cell activation/fibrosis control in animal models of muscular dystrophy. Fulfillment of the studies in this project will advance the biology of MG53 in muscle injury-repair and regeneration, and lay the foundation for our translational approach for targeting MG53 function for treatment of muscular dystrophy.

概括骨骼肌损伤修复和再生是一个多细胞过程，涉及急性损伤的修复肌膜、动员卫星细胞来替代丢失的肌纤维以及控制纤维化重塑以维持肌肉完整性，在肌营养不良症、肌膜完整性受损或膜修复引发肌肉退化级联，导致进行性、严重的发病率和开发治疗方法以改善肌膜完整性，同时促进死亡率。受伤肌纤维的再生仍然是肌肉生理学研究的主要挑战。基于 TRIM 家族蛋白成员 MG53 的发现，MG53 是细胞的重要组成部分 MG53 在囊泡运输中发挥作用并促进细胞内成核。囊泡到膜破坏部位以形成修复斑块，天然 MG53 存在于血液循环中，与肌肉损伤或分泌活性直接相关的水平。 MG53 (rhMG53) 蛋白可保护肌纤维和干细胞免受损伤，并减少肌肉纤维化 mdx 小鼠模型。过去几年我们对 MG53 的研究已经建立了一个潜在的三功能模型。 MG53 在肌肉损伤再生中的作用，作为修复急性肌膜损伤的促进剂，是在肌肉损伤的早期阶段激活卫星细胞，并通过控制来调节纤维化我们设想，成纤维细胞分化与慢性肌肉损伤相关。 MG53 将比当前治疗肌营养不良症的范例具有优势在目标 1 中，我们将。确定将新鉴定的 MG53 肌因子功能转导卫星激活的途径细胞对急性肌肉损伤的反应；定义了 MG53 调节功能的机制；慢性肌肉损伤期间的纤维化；并测试非侵入性干预措施是否可以调节循环 MG53 如果循环中的 MG53 在卫星细胞激活中发挥作用，我们预测。缺血预处理释放 MG53 而不会造成肌肉损伤，或诱导分泌 MG53 转基因小鼠模型将有效激活损伤后的卫星细胞和肌肉再生。 2、我们将评估循环中持续升高MG53以保护肌肉的安全性和有效性肌营养不良动物模型的完整性/卫星细胞激活/纤维化控制。该项目的研究将推进 MG53 在肌肉损伤修复和再生方面的生物学研究，并奠定基础为我们靶向 MG53 功能治疗肌营养不良症的转化方法奠定了基础。