Modulation of MG53 Function in Cardiac Membrane Repair

MG53 在心肌膜修复中的功能调节

• 批准号: 9027869
• 负责人: Jianjie Ma
• 金额: $ 38.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027869
• 关键词: Ablation; Acute; Acute myocardial infarction; Affect; Age; Animal Model; Area; Arrhythmia; Binding; Binding Sites; Biological Process; Biology; Biomedical Research; Boxing; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cellular Stress; Cessation of life; Chemicals; DYSF gene; Data; Defect; Emergency Situation; Emergency response; Event; Genetic; Heart; Heart Diseases; Heart Injuries; Heart failure; Histocytochemistry; Human; Human body; Injury; Ischemia; Link; Mechanics; Mediating; Membrane; Membrane Lipids; Molecular; Motor; Movement; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Myosin ATPase; Natural regeneration; Pathology; Phenotype; Physiological; Physiology; Play; Predisposition; Preparation; Process; Proteins; Publishing; Regenerative Medicine; Reperfusion Therapy; Research; Role; Site; Skeletal Muscle; Strenuous Exercise; Stress; Striated Muscles; System; TRIM Family; Testing; Therapeutic Agents; Tissues; Transgenic Organisms; Transition Elements; Translating; Vesicle; Wound Healing; Zinc; Zinc deficiency; base; caveolin-3; cellular imaging; insight; mouse model; novel; overexpression; oxidation; prevent; protective effect; repaired; response; sensor; tissue regeneration; trafficking; young adult

DESCRIPTION (provided by applicant): An emerging concept in recent biomedical research establishes that intrinsic membrane repair/regeneration is a fundamental aspect of normal human physiology and that disruption of this repair function underlies the progression of several pathologies, including cardiovascular diseases. We recently discovered that MG53, a muscle-specific TRIM-family protein, is an essential component of the acute membrane repair machinery in striated muscle. While genetic ablation of MG53 does not induce significant abnormality in young adult mice under non-stress conditions, increased susceptibility to ischemia and strenuous exercise-induced damage is evident in the MG53-/- hearts. Similar to skeletal muscle, damage to the cardiac membrane by mechanical, electrical or chemical insults leads to rapid translocation of MG53 toward the injury sites. The mg53-/- mice display arrhythmias even under normal physiological conditions, which may contribute to the elevated injury associated with stress. This stress-dependent cardiac phenotype raises the question how MG53 and other membrane repair molecules stand ready to rescue the cell from stress-induced membrane disruption as an emergency repair response. Aim 1 of our proposed studies will explore the mechanism underlying MG53-mediated repair of membrane damage to cardiomyocytes under conditions of ischemia, arrhythmias or acute injury, and establish that MG53 functions as an emergency response component for cardioprotection. MG53 contains the signature RING and B-Box motifs that constitute potential zinc (Zn) binding sites. Zn is one of the most abundant transition metals in the human body, and it is responsible for a wide range of biological functions including wound-healing. Several studies have linked Zn deficiency to cardiac dysfunction in conditions of ischemia-reperfusion and heart failure. Published studies from our group demonstrate that Zn has significant protective effect on acute myocardial infarction and arrhythmias, whereas the molecular mechanism underling cardioprotection by Zn is largely unknown. We have preliminary data to show that Zn-binding to MG53 plays a crucial role in MG53-mediated cell membrane repair. Aim 2 of our proposed studies will elucidate the molecular mechanism underlying the interaction of Zn with the RING/B-Box motifs of MG53 in regulating the nucleation process for MG53-mediated cell membrane repair in cardiac muscle. We anticipate that completion of the proposed studies will provide insights into the cardioprotective role of MG53 and its interaction with Zn in preventing damage to the cardiac membrane. Our studies will have broader impact on the basic biology of cell membrane repair and tissue regeneration, and have potential translational value for treatment of cardiovascular diseases.

描述（由申请人提供）：最近的生物医学研究中的一个新兴概念表明，内在的膜修复/再生是正常人类生理学的基本方面，并且这种修复功能的破坏构成了包括心血管疾病在内的几种病理学的发展。我们最近发现，MG53是一种肌肉特异性的修剪蛋白，是横纹肌中急性膜修复机械的重要组成部分。虽然MG53的遗传消融不会在非压力条件下引起年轻小鼠的明显异常，但在MG53 - / - 心脏中显而易见的是缺血的易感性，并且剧烈的运动引起的损害显而易见。与骨骼肌相似，机械，电或化学侮辱对心脏膜的损害会导致MG53迅速转移到损伤部位。即使在正常的生理条件下，MG53 - / - 小鼠也会表现出心律不齐，这可能导致与压力相关的损伤升高。这种依赖压力的心脏表型提出了一个问题，该问题是如何准备将细胞从应力诱导的膜破坏中挽救细胞作为紧急修复反应的问题。我们提出的研究的目标1将探讨MG53介导的膜损害对心肌细胞损害的机制，在缺血，心律不齐或急性损伤的情况下，并确定MG53作为心脏保护的紧急响应成分。 MG53包含构成潜在锌（Zn）结合位点的签名环和B盒基序。 Zn是人体中最丰富的过渡金属之一，它负责多种生物学功能，包括伤口愈合。在缺血 - 重新灌注和心力衰竭的情况下，几项研究将Zn缺乏症与心脏功能障碍联系起来。我们小组发表的研究表明，Zn对急性心肌梗塞和心律不齐具有显着的保护作用，而锌通过Zn进行心脏保护的分子机制在很大程度上是未知的。我们有初步的数据表明，对MG53的Zn结合在MG53介导的细胞膜修复中起着至关重要的作用。我们提出的研究的目标2将阐明Zn与MG53的环/B盒基序相互作用的分子机制，以调节心肌中MG53介导的细胞膜修复的成核过程。 我们预计，拟议的研究的完成将提供有关MG53的心脏保护作用及其与Zn相互作用在防止心脏膜损害方面的见解。我们的研究将对细胞膜修复和组织再生的基本生物学产生更广泛的影响，并具有治疗心血管疾病的潜在翻译价值。

项目成果

Dysfunction in the βII spectrin-dependent cytoskeleton underlies human arrhythmia.

• DOI: 10.1161/circulationaha.114.013708
• 发表时间: 2015-02-24
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Smith SA;Sturm AC;Curran J;Kline CF;Little SC;Bonilla IM;Long VP;Makara M;Polina I;Hughes LD;Webb TR;Wei Z;Wright P;Voigt N;Bhakta D;Spoonamore KG;Zhang C;Weiss R;Binkley PF;Janssen PM;Kilic A;Higgins RS;Sun M;Ma J;Dobrev D;Zhang M;Carnes CA;Vatta M;Rasband MN;Hund TJ;Mohler PJ
• 通讯作者: Mohler PJ

MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning

• DOI: 10.1161/circulationaha.110.954628
• 发表时间: 2010-06-15
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Cao, Chun-Mei;Zhang, Yan;Xiao, Rui-Ping
• 通讯作者: Xiao, Rui-Ping

CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice.

• DOI: 10.1038/mt.2015.192
• 发表时间: 2016-03
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Li Xu;K. Park;Lixia Zhao;Jing Xu;Mona El Refaey;Yandi Gao;Hua Zhu;Jianjie Ma;Renzhi Han

Treatment of acute lung injury by targeting MG53-mediated cell membrane repair.

• DOI: 10.1038/ncomms5387
• 发表时间: 2014-07-18
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jia, Yanlin;Chen, Ken;Lin, Peihui;Lieber, Gissela;Nishi, Miyuki;Yan, Rosalie;Wang, Zhen;Yao, Yonggang;Li, Yu;Whitson, Bryan A.;Duann, Pu;Li, Haichang;Zhou, Xinyu;Zhu, Hua;Takeshima, Hiroshi;Hunter, John C.;McLeod, Robbie L.;Weisleder, Noah;Zeng, Chunyu;Ma, Jianjie
• 通讯作者: Ma, Jianjie

Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury.

• DOI: 10.3390/ijms17050662
• 发表时间: 2016-05-03
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Duann P;Lianos EA;Ma J;Lin PH
• 通讯作者: Lin PH