Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
基本信息
- 批准号:8450107
- 负责人:
- 金额:$ 34.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffectBindingCardiacCardiac Muscle ContractionCardiomyopathiesDepressed moodDevelopmentDiagnosisDiseaseDissociationEnergy TransferEnvironmentFluorescence AnisotropyFluorescence SpectroscopyGoalsHeadHealthHeartHeart failureHumanKineticsKnowledgeMeasurementMeasuresMechanicsMethodologyMicrofilamentsMolecularMonitorMuscleMuscle CellsMuscle FibersMuscle functionMuscle relaxation phaseMutagenesisMutationMyocardiumMyofibrilsMyosin ATPaseNucleic Acid Regulatory SequencesOutcomePhosphorylationPlayPreparationPreventionProcessProgress ReportsProteinsRecombinant ProteinsRegulationRelaxationResearchRoleSarcomeresSeriesSignal TransductionSkinStructural ProteinStructureTechniquesTestingThick FilamentThin FilamentTroponinTroponin CTroponin IWorkbaseheart functionimprovedinnovationinterdisciplinary approachnovelnovel strategiespreventprotein protein interactionpublic health relevancereconstitutionresponsetransmission process
项目摘要
DESCRIPTION (provided by applicant): Heart failure can be a result of impaired cardiac contraction or relaxation or both, which are regulated by Ca2+induced thin filament activation and deactivation. Therefore, understanding the mechanism of thin filament regulation is of great importance in prevention and treatment of heart failure. The molecular basis of the thin filament regulation involves Ca2+induced alterations in the structure and structural kinetics and dynamics associated with the protein-protein interactions at the interface between troponin and actin. The objective of this proposal is to define the detailed kinetic mechanism that underlies Ca2+induced thin filament activation/deactivation and how it is affected by troponin phosphorylation and cardiomyopathy mutations found in cTnI. To achieve the goal, this proposal will address the following questions: 1) What is the kinetic role of different functional regions of cTnI in regulating crossbridge kinetics? 2) How do the structural dynamics of the cTnI C-domain play roles in thin filament regulation? and 3) How are the structural changes and structural kinetics of the thin filament modified in the skinned muscle fibers and myofibrils? The underlying hypothesis of this proposal is that the Ca2+induced structural transitions involving the different regions of troponin I at the interface between troponin and actin play different roles in regulating kinetics of the interaction between actin and mysoin, and the structural transitions can be affected by strong crossbridges, cardiomyopathy mutations, and phosphorylation of troponin proteins, as well as cellular lattice environment found in intact muscle cells. This project capitalizes on our FRET and fluorescence anisotropy expertise in determining protein structural kinetics and dynamics to exploit a new approach by implementing FRET methodologies into muscle fibers and myofibril measurements. This will enable us to acquire the urgently needed kinetic and dynamic information associated with the Ca2+induced thin filament regulation on muscle function. The results from this study will have a positive impact by advancing our understanding of the regulatory role of cardiac thin filament in cardiac muscle contraction and relaxation in health and disease.
描述(由申请人提供):心力衰竭可能是心脏收缩或舒张受损或两者兼而有之的结果,其受Ca 2+诱导的细丝激活和失活调节。因此,了解细纤维调节机制对心力衰竭的防治具有重要意义。细丝调节的分子基础涉及Ca 2+诱导的结构和结构动力学改变以及与肌钙蛋白和肌动蛋白之间界面处的蛋白质-蛋白质相互作用相关的动力学。本提案的目的是确定Ca 2+诱导的细丝激活/失活的详细动力学机制,以及肌钙蛋白磷酸化和cTnI中发现的心肌病突变如何影响该机制。为了实现这一目标,本提案将解决以下问题:1)肌钙蛋白I不同功能区域在调节过桥动力学中的动力学作用是什么?2)cTnI C结构域的结构动力学如何在细丝调节中发挥作用?(3)在带皮肌纤维和肌原纤维中,细丝的结构变化和结构动力学如何?该提议的基本假设是,涉及肌钙蛋白和肌动蛋白之间界面处的肌钙蛋白I的不同区域的Ca 2+诱导的结构转变在调节肌动蛋白和肌球蛋白之间相互作用的动力学中发挥不同的作用,并且结构转变可以受到强横桥、心肌病突变和肌钙蛋白蛋白磷酸化的影响,以及在完整肌肉细胞中发现的细胞晶格环境。该项目利用我们在确定蛋白质结构动力学和动力学方面的FRET和荧光各向异性专业知识,通过将FRET方法应用于肌纤维和肌原纤维测量来开发新方法。这将使我们能够获得迫切需要的动力学和动力学信息与钙离子诱导的细丝调节肌肉功能。这项研究的结果将通过促进我们对心脏细丝在健康和疾病中心肌收缩和舒张中的调节作用的理解产生积极的影响。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cationic isotachophoresis separation of the biomarker cardiac troponin I from a high-abundance contaminant, serum albumin.
- DOI:10.1002/elps.201400009
- 发表时间:2014-07
- 期刊:
- 影响因子:2.9
- 作者:Jacroux, Thomas;Bottenus, Danny;Rieck, Bennett;Ivory, Cornelius F.;Dong, Wen-ji
- 通讯作者:Dong, Wen-ji
Förster resonance energy transfer structural kinetic studies of cardiac thin filament deactivation.
Förster 心脏细丝失活的共振能量转移结构动力学研究。
- DOI:10.1074/jbc.m808075200
- 发表时间:2009
- 期刊:
- 影响因子:0
- 作者:Xing,Jun;Jayasundar,JayantJ;Ouyang,Yexin;Dong,Wen-Ji
- 通讯作者:Dong,Wen-Ji
FRET study of the structural and kinetic effects of PKC phosphomimetic cardiac troponin T mutants on thin filament regulation.
FRET 研究 PKC 磷酸模拟心肌肌钙蛋白 T 突变体对细丝调节的结构和动力学影响。
- DOI:10.1016/j.abb.2014.03.013
- 发表时间:2014
- 期刊:
- 影响因子:3.9
- 作者:Schlecht,William;Zhou,Zhiqun;Li,King-Lun;Rieck,Daniel;Ouyang,Yexin;Dong,Wen-Ji
- 通讯作者:Dong,Wen-Ji
Preconcentration and detection of the phosphorylated forms of cardiac troponin I in a cascade microchip by cationic isotachophoresis.
- DOI:10.1039/c1lc20469f
- 发表时间:2011-11-21
- 期刊:
- 影响因子:6.1
- 作者:Bottenus D;Hossan MR;Ouyang Y;Dong WJ;Dutta P;Ivory CF
- 通讯作者:Ivory CF
Enzymatic amplification of DNA/RNA hybrid molecular beacon signaling in nucleic acid detection.
- DOI:10.1016/j.ab.2012.09.015
- 发表时间:2013-01-15
- 期刊:
- 影响因子:2.9
- 作者:Jacroux T;Rieck DC;Cui R;Ouyang Y;Dong WJ
- 通讯作者:Dong WJ
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WEN-JI DONG其他文献
WEN-JI DONG的其他文献
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{{ truncateString('WEN-JI DONG', 18)}}的其他基金
Paper-Based Nucleic Acid Amplification Test for Rapid Diagnosis of Hepatitis C Viral Infection
纸基核酸扩增测试快速诊断丙型肝炎病毒感染
- 批准号:
10558611 - 财政年份:2022
- 资助金额:
$ 34.73万 - 项目类别:
Paper-Based Nucleic Acid Amplification Test for Rapid Diagnosis of Hepatitis C Viral Infection
纸基核酸扩增测试快速诊断丙型肝炎病毒感染
- 批准号:
10430557 - 财政年份:2022
- 资助金额:
$ 34.73万 - 项目类别:
Two-Dimensional Multi-Stage Isotachophoretic Technology for Multiplex Analysis of Cancer Exosomes and Proteins Marker Panel
用于癌症外泌体和蛋白质标记物组多重分析的二维多级等速电泳技术
- 批准号:
10322022 - 财政年份:2021
- 资助金额:
$ 34.73万 - 项目类别:
Structural Kinetics of Thin Filament Regulation at Single Molecule Level
单分子水平细丝调控的结构动力学
- 批准号:
8445988 - 财政年份:2013
- 资助金额:
$ 34.73万 - 项目类别:
Structural Kinetics of Thin Filament Regulation at Single Molecule Level
单分子水平细丝调节的结构动力学
- 批准号:
8690957 - 财政年份:2013
- 资助金额:
$ 34.73万 - 项目类别:
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