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
基本信息
- 批准号:9889409
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAgingAnimal ModelAreaAwardBiologyCardiacCardiac MyocytesCardiomyopathiesCellsChronicCongestive Heart FailureCouplingDataDisabled PersonsElectrophysiology (science)FailureFunctional disorderGeneticGoalsHealthHealthcare SystemsHeartHeart DiseasesHeart HypertrophyHeart failureHumanImaging TechniquesImpairmentIn SituInjuryKnock-inKnowledgeLeft ventricular structureMediatingMembraneModelingMolecularMolecular BiologyMusMuscleMuscle CellsMyocardialMyocardial IschemiaNuclearOutcomeOverdosePathogenesisPathologicPathologyPatient-Focused OutcomesPatientsPilot ProjectsProcessProtein FamilyProteinsRegulationResearchResourcesRoleSarcoplasmic ReticulumSeminalSignal TransductionStressStructural ProteinStructureSurfaceSystemTRIM MotifTestingTherapeuticTranscriptional ActivationTranscriptional RegulationTreatment FailureUp-RegulationVesicleVeteransbasecardiogenesiscare costsconfocal imagingdesignheart functionhuman modelimprovedinsightinterdisciplinary approachjunctophilinmouse modelmutantmyocyte-specific enhancer-binding factor 2noveloverexpressionpressureprogramsrepairedresponseside effecttargeted treatmenttraffickingtranscription factorubiquitin-protein ligase
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Long-Sheng Song其他文献
Long-Sheng Song的其他文献
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{{ truncateString('Long-Sheng Song', 18)}}的其他基金
ERK1/2-Integrin Signaling in Desmosome-Dyad Crosstalk
桥粒-二元串扰中的 ERK1/2-整合素信号转导
- 批准号:
10198251 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Molecular Determinants of MG53 in Heart Structure and Function
MG53 在心脏结构和功能中的分子决定因素
- 批准号:
10685305 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Molecular Determinants of MG53 in Heart Structure and Function
MG53 在心脏结构和功能中的分子决定因素
- 批准号:
10199214 - 财政年份:2021
- 资助金额:
-- - 项目类别:
ERK1/2-Integrin Signaling in Desmosome-Dyad Crosstalk
桥粒-二元串扰中的 ERK1/2-整合素信号转导
- 批准号:
10687055 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart
E-C 偶联结构蛋白 Junctophilin-2 在心脏中的新功能
- 批准号:
10478204 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Oxidative Stress, PKC Signaling and Heart Failure
氧化应激、PKC 信号传导和心力衰竭
- 批准号:
9029006 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart
E-C 偶联结构蛋白 Junctophilin-2 在心脏中的新功能
- 批准号:
10058735 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Novel Functions of the E-C Coupling Structural Protein Junctophilin-2 in the Heart
E-C 偶联结构蛋白 Junctophilin-2 在心脏中的新功能
- 批准号:
10689197 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Novel functions of E-C coupling structural protein junctophilin-2 in the heart
E-C耦合结构蛋白junctophilin-2在心脏中的新功能
- 批准号:
9199431 - 财政年份:2016
- 资助金额:
-- - 项目类别:
T-tubule remodeling and Ca2+-dependent arrhythmogenesis in cardiomyopathies.
心肌病中的 T 管重塑和 Ca2 依赖性心律失常发生。
- 批准号:
7837390 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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