Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation

心肌肌球蛋白结合蛋白-C:结构、功能和调节

基本信息

项目摘要

Mutations in cardiac myosin binding protein-C (cMyBP-C) lead to sudden death in young individuals with Familial Hypertrophic Cardiomyopathy. Despite Its clinical importance and its association with the actomyosin molecular motor of the heart, a significant gap still remains in understanding how cMyBP-C modulates cardiac power production. In addition, cMyBP-C is phosphorylated following p-adrenergic stimulation, suggesting that cMyBP-C Itself may be regulated in a phosphorylation-dependent manner. This Program Project (3 projects and 3 cores) will provide a comprehensive molecular understanding of cMyBP-C function, its regulation by phosphorylation, and its impact on cardiac contractility. Using state-ofthe- art techniques, we will characterize cMyBP-C's structure and function through studies ranging from the mechanics of the whole heart down to interactions between a single cMyBP-C molecule and the actomyosin molecular motor. Project #1 will use high resolution 3-dimensional electron microscopic reconstruction to characterize the structure of cMyBP-C and its sarcomeric organization, providing insight to its functional capacity. Project #2 will use the laser trap to assess cMyBP-C's ability to modulate actomyosin power production at the single molecule level, while Project #3 will use transgenic mouse models to define the role of cMyBP-C's putative actin-binding and its phosphorylation on cardiac function under various physiological conditions. The Ventricular and Cardiac Fiber Characterization and Integration Core (Core B) will gather the ventricular performance and fiber mechanical data to bridge the physiological gap between the single molecule and whole animal studies. In addition, the Core will provide a modeling platform to integrate the data from all physiological levels into a mechanistic model of cMyBP-C functionality. The Mouse and cMyBP-C Protein Production Core (Core C) will generate mice with mutant cMyBP-C and in vitro expression of mutant cMyBP-C protein at its actin-binding and phosphorylation domains. These hearts and protein will be studied at all anatomical levels by the various projects. The Program Project's long term goals are to: 1) define cMyBP-C's molecular structure and sarcomeric organization; 2) determine how cMyBP-C modulates cardiac function in a phosphorylation-dependent manner; 3) define why alterations in cMyBP-C phosphorylation are associated with heart failure in humans.
心肌肌球蛋白结合蛋白c (cMyBP-C)突变可导致年轻人猝死

项目成果

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David M Warshaw其他文献

David M Warshaw的其他文献

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{{ truncateString('David M Warshaw', 18)}}的其他基金

Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
  • 批准号:
    10393000
  • 财政年份:
    2021
  • 资助金额:
    $ 205.49万
  • 项目类别:
Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
  • 批准号:
    10204620
  • 财政年份:
    2021
  • 资助金额:
    $ 205.49万
  • 项目类别:
Equipment supplement - Refeyn TwoMP iSCAT microscope
设备补充 - Refeyn TwoMP iSCAT 显微镜
  • 批准号:
    10784112
  • 财政年份:
    2021
  • 资助金额:
    $ 205.49万
  • 项目类别:
Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
  • 批准号:
    10605333
  • 财政年份:
    2021
  • 资助金额:
    $ 205.49万
  • 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
  • 批准号:
    8860500
  • 财政年份:
    2015
  • 资助金额:
    $ 205.49万
  • 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
  • 批准号:
    9128036
  • 财政年份:
    2015
  • 资助金额:
    $ 205.49万
  • 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
  • 批准号:
    9282730
  • 财政年份:
    2015
  • 资助金额:
    $ 205.49万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    8215311
  • 财政年份:
    2011
  • 资助金额:
    $ 205.49万
  • 项目类别:
Myosin Va and VI Cargo Transport: In Vitro Model Systems
肌球蛋白 Va 和 VI 货物运输:体外模型系统
  • 批准号:
    8103714
  • 财政年份:
    2011
  • 资助金额:
    $ 205.49万
  • 项目类别:
Myosin Va and VI Cargo Transport: In Vitro Model Systems
肌球蛋白 Va 和 VI 货物运输:体外模型系统
  • 批准号:
    8248783
  • 财政年份:
    2011
  • 资助金额:
    $ 205.49万
  • 项目类别:

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