Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
基本信息
- 批准号:7841314
- 负责人:
- 金额:$ 17.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-15 至 2011-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffectBackBindingBinding SitesBiochemicalBiological AssayCardiacCardiac Muscle ContractionCardiomyopathiesComplexContractile ProteinsCoupledCyclic AMP-Dependent Protein KinasesDataDevelopmentDiagnosisDiseaseDissociationEnergy TransferEquilibriumEventFailureFiberGoalsHeartHeart failureIn VitroIndividualKineticsKnowledgeLeadMeasurementMicrofilamentsModificationMolecularMolecular ConformationMonitorMovementMuscleMuscle ContractionMuscle FibersMuscle functionMyocardiumMyofibrilsMyosin ATPaseMyosin S-1N DomainNucleic Acid Regulatory SequencesPhosphorylationPhosphorylation SitePlayPost-Translational Protein ProcessingProcessProtein IsoformsProtein Kinase CProteinsRegulationRelaxationReportingResearchResearch PersonnelRoleSeriesSignal TransductionSiteSkinStriated MusclesStructureStudy modelsSurfaceSystemTestingThermodynamicsThin FilamentTimeTitrationsTo specifyTropomyosinTroponin CTroponin Ibasedesignfeedinggenetic regulatory proteininformation processingmutantpreventprogramsreconstitutionresearch studyresponseskeletaltransmission process
项目摘要
DESCRIPTION (provided by applicant): Force development during striated muscle contraction is initiated by the binding of Ca2+ to the specific sites in troponin C (TnC), triggering a series of functional structural changes within the thin filament, including opening of the N-domain of TnC, conformational change of the inhibitory region of troponin I (Tnl), and switching interaction between Tnl and actin to Tnl and TnC, which ultimately lead to a cyclic interaction between actin and myosin to form strong force-generating cross-bridges. Full muscle activation requires both Ca2+ binding and feed back modulation of cross-bridge cycling. In cardiac muscle it is also modulated by protein phosphorylation which plays important roles in heart failing/hypertrophic process. To fully understand muscle regulatory mechanism requires structural, thermodynamic and kinetic information on each of these structural transitions during force development. My long-term research goal is to elucidate the kinetics of movements of the thin finlament betweem extremes of contraction/relaxation, and understand how they are modified by cross-bridge cycling and phosphorylation. To achieve the goal, this proposal addresses the following three issues: (1) What is the kinetics of each individual activation/deactivation process of the thin filament? (2) How does the cross-bridge cycling affect these kinetic processes? And (3) what is the role of phsophorylation in modulating these transitions? Newly designed conformational markers based on Forster resonance energy transfer to monitor these structural transitions will be used for stopped-flow kinetic and Ca2+ titration measurements at different activation conditions to acquire the desired information. These markers will be incorporated into reconstituted thin filament, myofibrils and skinned fibers along with/without phosphotylated proteins to specify the time-dependent changes of specific domain movements of the thin filament in response to Ca2+. Results of this study will enhance our understanding of molecular mechanisms of thin filament activation in response of Ca2+ and the role of protein phosphorylation in heart failure.
描述(申请人提供):肌钙蛋白C(TnC)的特异性位点与Ca 2+结合,引发肌丝内一系列功能性结构变化,包括肌钙蛋白I(TnI)抑制区的构象变化,以及TnI和肌动蛋白之间的相互作用转换为TnI和TnC,其最终导致肌动蛋白和肌球蛋白之间的循环相互作用以形成产生强力的横桥。完全的肌肉激活需要Ca 2+结合和跨桥循环的反馈调节。在心肌中,它也受到蛋白磷酸化的调节,蛋白磷酸化在心力衰竭/肥大过程中起重要作用。为了充分了解肌肉的调节机制,需要在力的发展过程中,这些结构转换的结构,热力学和动力学信息。我的长期研究目标是阐明薄鳍片在收缩/松弛极端之间的运动动力学,并了解它们是如何被跨桥循环和磷酸化修饰的。为了实现这一目标,该提议解决了以下三个问题:(1)细长丝的每个单独的活化/失活过程的动力学是什么?(2)跨桥自行车如何影响这些动力学过程?磷酸化在调节这些转变中的作用是什么?新设计的构象标记物的基础上福斯特共振能量转移,以监测这些结构转变将用于停流动力学和Ca 2+滴定测量在不同的激活条件下,以获得所需的信息。这些标记物将与/不与磷酸化蛋白一起掺入重构的细丝、肌原纤维和带皮纤维中,以指定响应于Ca 2+的细丝的特定结构域运动的时间依赖性变化。本研究的结果将增强我们对细纤维激活的分子机制的理解,以响应Ca 2+和蛋白质磷酸化在心力衰竭中的作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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WEN-JI DONG其他文献
WEN-JI DONG的其他文献
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