Kinetics of Cardiac Myofilament Activation

心肌丝激活动力学

基本信息

  • 批准号:
    6905197
  • 负责人:
  • 金额:
    $ 36.25万
  • 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 2005-12-31
  • 项目状态:
    已结题

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):在横纹肌收缩过程中,肌钙与肌钙蛋白C(TNC)的特定部位结合,引发细丝内一系列功能结构的变化,包括TNC的N-结构域的开放,肌钙蛋白I(TnL)抑制区的构象变化,以及TnL和肌动蛋白之间的相互作用切换到TnL和TNC,最终导致肌动蛋白和肌球蛋白之间的循环相互作用,形成强大的生力交叉桥梁。充分的肌肉激活既需要钙离子结合,也需要跨桥循环的反馈调制。在心肌中,它也受到蛋白磷酸化的调节,在心力衰竭/肥大过程中发挥着重要作用。为了充分了解肌肉调节机制,需要了解力量发展过程中每一种结构转变的结构、热力学和动力学信息。我的长期研究目标是阐明细丝在收缩/松弛极端之间的运动动力学,并了解它们是如何通过跨桥循环和磷酸化来修改的。为了实现这一目标,该方案解决了以下三个问题:(1)细丝每个单独的激活/去活过程的动力学是什么?(2)跨桥循环如何影响这些动力学过程?以及(3)磷酸化在调节这些转变中的作用是什么?新设计的基于Forster共振能量转移的构象标记用于监测这些结构转变,将用于不同活化条件下的停流动力学和钙滴定测量,以获得所需的信息。这些标记物将被结合到重组的细丝、肌原纤维和有/没有磷酸化蛋白的皮肤纤维中,以确定细丝的特定结构域运动对钙离子的响应随时间的变化。这一研究结果将加深我们对钙离子响应细丝激活的分子机制以及蛋白磷酸化在心力衰竭中的作用的理解。

项目成果

期刊论文数量(0)
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WEN-JI DONG其他文献

WEN-JI DONG的其他文献

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{{ 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:
    $ 36.25万
  • 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:
    $ 36.25万
  • 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:
    $ 36.25万
  • 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:
    $ 36.25万
  • 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:
    $ 36.25万
  • 项目类别:
Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
  • 批准号:
    7841314
  • 财政年份:
    2009
  • 资助金额:
    $ 36.25万
  • 项目类别:
Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
  • 批准号:
    7393797
  • 财政年份:
    2005
  • 资助金额:
    $ 36.25万
  • 项目类别:
Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
  • 批准号:
    7031005
  • 财政年份:
    2005
  • 资助金额:
    $ 36.25万
  • 项目类别:
Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
  • 批准号:
    7597232
  • 财政年份:
    2005
  • 资助金额:
    $ 36.25万
  • 项目类别:
Kinetics of Cardiac Myofilament Activation
心肌丝激活动力学
  • 批准号:
    8450107
  • 财政年份:
    2005
  • 资助金额:
    $ 36.25万
  • 项目类别:

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