Cardiac Myosin Binding Protein-C: Structure and Function

心肌肌球蛋白结合蛋白-C:结构和功能

基本信息

  • 批准号:
    9391433
  • 负责人:
  • 金额:
    $ 39.15万
  • 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:
    2016-12-01 至 2020-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cardiac myosin binding protein-C (cMyBP-C) is a trans-filament protein which, at its N'-region, connects thick and thin filaments to regulate cardiac contractility. The overall objective of the studies contained in this renewal of R01HL-105826 is to define the N'-region of cMyBP-C as a critical regulator of cardiac contractility. In particular, C0-C1f, which interacts only with actin, is generated by proteolysis of cMyBP-C during ischemia/reperfusion (I/R) injury and heart failure. On the other hand, C0-C2 interacts with both actin and myosin, connecting thin and thick filaments to regulate sarcomere function. On the basis of these findings, we will 1) use a novel transgenic mouse model expressing cMyBP-C (cMyBP-C110kDa) in which the C0-C1f region was ablated to study the necessity and sufficiency of this domain in regulating cardiac contractility and 2) use adeno-associated virus 9 (AAV9)-mediated expression of (i) recombinant C0-C2 to determine the sufficiency of N'-terminal C0-C2 in bundling thick and thin filaments in vivo and (ii) recombinant C0-C2ΔCTS, in which the calpain-targeted site (CTS) has been ablated, to determine its therapeutic potential in improving cardiac function pre- and post-I/R injury. The molecular mechanisms underlying the regulation of cMyBP-C and, in turn, its impact on sarcomere structure and function, are largely unknown. Our short-term goal is to elucidate the specific role(s) of the N'-region of cMyBP-C in the regulation of cardiac function, whereas our long-term goal is to determine the mechanisms by which cMyBP-C stabilizes sarcomeric structure and function, thereby conferring cardioprotection during I/R injury. SPECIFIC AIM 1 will test the hypothesis that the C0-C1f domain of cMyBP-C, which is cleaved and released during I/R injury, is necessary for regulating cardiac function. Transgenic cMyBP-C110kDa mice will be used to determine the critical role of the N'-region of cMyBP-C at the sarcomere and whole-heart levels, compared to the control non-transgenic mice. SPECIFIC AIM 2 will test the hypothesis that the C0-C2 domains of cMyBP-C are sufficient to bundle thick and thin filaments and to regulate normal cardiac function. AAV9-mediated expression of recombinant C0-C2 will be used to prevent or rescue contractile dysfunction in mouse models that lack either the N'-region (C0-C1f) or full-length cMyBP-C in vivo. SPECIFIC AIM 3 will test the hypothesis that expression of recombinant C0-C2ΔCTS in vivo confers cardioprotection during I/R injury. Recombinant C0-C2ΔCTS protein is protected from calpain-mediated degradation. We expect AAV9-mediated expression of recombinant C0-C2ΔCTS to significantly reduce infarct size and apoptosis, as well as preserve contractile function during I/R injury. Together, these studies will determine the necessity and sufficiency of the N'-region (both C0-C1f and C0-C2) of cMyBP-C to regulate cardiac function, and, hence, provide therapy for myocardial injury and heart failure occurring during I/R injury.
描述(由申请人提供):心肌肌球蛋白结合蛋白-C(cMyBP-C)是一种反式丝蛋白,其在其N'-区域连接粗丝和细丝以调节心肌收缩力。 R01HL-105826 更新中包含的研究的总体目标是将 cMyBP-C 的 N' 区定义为心肌收缩力的关键调节因子。特别是,C0-C1f 仅与肌动蛋白相互作用,是由缺血/再灌注 (I/R) 损伤和心力衰竭期间 cMyBP-C 的蛋白水解产生的。另一方面,C0-C2 与肌动蛋白和肌球蛋白相互作用,连接细丝和粗丝以调节肌节功能。基于这些发现,我们将 1) 使用表达 cMyBP-C (cMyBP-C110kDa) 的新型转基因小鼠模型,其中 C0-C1f 区域被消融,以研究该结构域在调节心肌收缩力方面的必要性和充分性;2) 使用腺相关病毒 9 (AAV9) 介导的 (i) 重组 C0-C2 的表达来确定 N' 端的充分性 C0-C2 在体内捆绑粗丝和细丝,以及 (ii) 重组 C0-C2ΔCTS,其中钙蛋白酶靶向位点 (CTS) 已被消融,以确定其在改善 I/R 损伤前后心脏功能的治疗潜力。 cMyBP-C 调节的分子机制及其对肌节结构和功能的影响在很大程度上尚不清楚。我们的短期目标是阐明cMyBP-C N'区在心脏功能调节中的具体作用,而我们的长期目标是确定cMyBP-C稳定肌节结构和功能的机制,从而在I/R损伤期间赋予心脏保护作用。 具体目标 1 将检验以下假设:cMyBP-C 的 C0-C1f 结构域在 I/R 损伤期间被裂解和释放,对于调节心脏功能是必需的。转基因 cMyBP-C110kDa 小鼠将用于确定与对照非转基因小鼠相比,cMyBP-C N'区在肌节和全心脏水平上的关键作用。 SPECIFIC AIM 2 将测试以下假设:cMyBP-C 的 C0-C2 结构域足以捆绑粗细丝并调节正常心脏功能。 AAV9 介导的重组 C0-C2 表达将用于预防或挽救体内缺乏 N' 区 (C0-C1f) 或全长 cMyBP-C 的小鼠模型的收缩功能障碍。具体目标 3 将检验重组 C0-C2ΔCTS 体内表达在 I/R 损伤期间提供心脏保护作用的假设。重组 C0-C2ΔCTS 蛋白免受钙蛋白酶介导的降解。我们预计 AAV9 介导的重组 C0-C2ΔCTS 表达能够显着减少梗塞面积和细胞凋亡,并在 I/R 损伤期间保留收缩功能。总之,这些研究将确定 cMyBP-C 的 N' 区(C0-C1f 和 C0-C2)调节心脏功能的必要性和充分性,从而为 I/R 损伤期间发生的心肌损伤和心力衰竭提供治疗。

项目成果

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Sakthivel Sadayappan其他文献

Sakthivel Sadayappan的其他文献

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{{ truncateString('Sakthivel Sadayappan', 18)}}的其他基金

Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
  • 批准号:
    10461813
  • 财政年份:
    2020
  • 资助金额:
    $ 39.15万
  • 项目类别:
Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
  • 批准号:
    10673945
  • 财政年份:
    2020
  • 资助金额:
    $ 39.15万
  • 项目类别:
Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
  • 批准号:
    10239247
  • 财政年份:
    2020
  • 资助金额:
    $ 39.15万
  • 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
  • 批准号:
    8705576
  • 财政年份:
    2012
  • 资助金额:
    $ 39.15万
  • 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
  • 批准号:
    9122471
  • 财政年份:
    2012
  • 资助金额:
    $ 39.15万
  • 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
  • 批准号:
    8352638
  • 财政年份:
    2012
  • 资助金额:
    $ 39.15万
  • 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
  • 批准号:
    8891482
  • 财政年份:
    2012
  • 资助金额:
    $ 39.15万
  • 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
  • 批准号:
    8516588
  • 财政年份:
    2012
  • 资助金额:
    $ 39.15万
  • 项目类别:
Cardiac Myosin Binding Protein-C: Structure and Function
心肌肌球蛋白结合蛋白-C:结构和功能
  • 批准号:
    8600985
  • 财政年份:
    2011
  • 资助金额:
    $ 39.15万
  • 项目类别:
Cardiac myosin binding protein-C: Structure and Function
心肌肌球蛋白结合蛋白-C:结构和功能
  • 批准号:
    9104884
  • 财政年份:
    2011
  • 资助金额:
    $ 39.15万
  • 项目类别:

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由actomyosin介导的集体性细胞迁移对唇腭裂发生的影响的研究
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核力反馈作为肌动球蛋白张力控制的变阻器
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    MR/Y001125/1
  • 财政年份:
    2024
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  • 项目类别:
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