Understanding the multifaceted functions of MG53 in heart failure pathogenesis

了解 MG53 在心力衰竭发病机制中的多方面功能

• 批准号: 9889409
• 负责人: Long-Sheng Song
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889409
• 关键词: Acute; Aging; Animal Model; Area; Award; Biology; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Chronic; Congestive Heart Failure; Coupling; Data; Disabled Persons; Electrophysiology (science); Failure; Functional disorder; Genetic; Goals; Health; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Imaging Techniques; Impairment; In Situ; Injury; Knock-in; Knowledge; Left ventricular structure; Mediating; Membrane; Modeling; Molecular; Molecular Biology; Mus; Muscle; Muscle Cells; Myocardial; Myocardial Ischemia; Nuclear; Outcome; Overdose; Pathogenesis; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pilot Projects; Process; Protein Family; Proteins; Regulation; Research; Resources; Role; Sarcoplasmic Reticulum; Seminal; Signal Transduction; Stress; Structural Protein; Structure; Surface; System; TRIM Motif; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Treatment Failure; Up-Regulation; Vesicle; Veterans; base; cardiogenesis; care costs; confocal imaging; design; heart function; human model; improved; insight; interdisciplinary approach; junctophilin; mouse model; mutant; myocyte-specific enhancer-binding factor 2; novel; overexpression; pressure; programs; repaired; response; side effect; targeted treatment; trafficking; transcription factor; ubiquitin-protein ligase

Heart failure is the most common health concern for aging veterans. At the cellular and molecular level, heart failure is the result of cardiomyocyte contractile failure due to impairment of cardiac excitation-contraction (E-C) coupling process. E-C coupling is the central mechanism governing cardiomyocyte contraction. One critical structural component of E–C coupling is the myocyte transverse (T)-tubule system. T-tubules are orderly invaginations of surface membrane into the cell interior and are critical for rapid electric excitation and synchronous triggering of sarcoplasmic reticulum Ca2+ release, and therefore, coordinated contraction of each contractile unit throughout the entire myocyte. In failing myocytes from animal models and human patients, we and others have shown that the regularly arrayed T-tubule system undergoes disruptive remodeling, leading to aberrant intracellular Ca2+ release and compromised myocyte contractility. A long-term goal of my research program is to achieve a better understanding of the mechanisms underlying T-tubule damage in different types of heart disease, and to identify new strategies that can restore or repair T-tubule integrity and thereby improve or even rescue cardiac function. Towards identifying putative mechanisms for T-tubule repair, we have detected increased expression of Mitsugumin 53 (MG53, also known as TRIM72) in human failing hearts and animal models of chronic heart failure. MG53 is a novel muscle-specific protein involved in membrane vesicle trafficking and membrane repair following acute injury. Our pilot data showed that exogenous MG53 overexpression in short term protects against T-tubule damage, but chronic long-term overexpression of MG53 results in severe T-tubule disruption. These seemingly opposite data led to the hypothesis that MG53-mediated membrane repair is necessary in the short term to protect against T-tubule damage in response to cardiac stress, whereas chronic long-term upregulation of MG53 leads to myocyte T-tubule membrane damage and E- C coupling dysfunction instead of membrane repair. We will test this hypothesis in three aims: 1) Determine the role of MG53 upregulation in T-tubule integrity and heart failure progression in cardiomyopathy; 2) Define the mechanisms by which MG53 regulates T-tubule integrity in cardiomyocytes; and 3) Determine the molecular mechanism of MG53 upregulation in heart failure. Our study will define the role for long-term upregulation of the membrane repair protein, MG53, in damage of the T-tubule membrane structure in human and mouse models, which is a completely unstudied area. Understanding these molecular mechanisms will provide a new platform and guide us to design better MG53/T-tubule-targeted therapeutics for heart failure treatment by promoting repairs while avoiding the side effects.

心脏衰竭是老年退伍军人最常见的健康问题。在细胞和分子水平上，心脏