cMyBPC and Regulation of Myocardial Contraction

cMyBPC 和心肌收缩的调节

基本信息

  • 批准号:
    7114287
  • 负责人:
  • 金额:
    $ 33.94万
  • 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:
    2005-09-01 至 2010-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long range goal of the proposed experiments is to understand the function of myosin binding protein-C in the regulation of cardiac contraction. Mutations in cardiac myosin binding protein-C (cMyBPC) account for nearly half of all instances of inherited hypertrophic cardiomyopathy and cMyBP-C is phosphorylated in response to inotropic stimuli, but neither the mechanisms by which mutations in cMyBP-C cause disease nor the role of cMyBP-C in mediating cardiac contractile responses are well understood. Until now the central difficulty in addressing the function of MyBP-C has been the inability to systematically alter cMyBP-C content or to selectively affect cMyBP-C phosphorylation state without simultaneously affecting other myofilament proteins. However, both these technical limitations will be overcome in the proposed experiments by using cMyBP-C knockout mice that lack cMyBP-C in heart. The cMyBP-C knockout mice therefore provide a "null" background on which to test specific mechanistic hypotheses of cMyBP-C function in health and disease. Based on our initial studies characterizing the cMyBP-C knockout mice, the working hypothesis guiding these experiments is that cMyBP-C normally acts to limit cross-bridge kinetics and power output and that phosphorylation of cMyBP-C relieves this inhibition. We further propose that the contractile effects of cMyBP-C are mediated by binding to myosin at two distinct sites and effects elicited by cMyBP-C binding differ depending on whether one or both sites are occupied. As a corollary to this idea, we propose that unregulated binding of the cMyBP-C N-terminus to myosin S2, as might occur in some familial hypertrophic cardiomyopathies, is sufficient to cause cardiomyopathy. These hypotheses will be tested in four Specific Aims designed to determine 1) contractile effects of cMyBP-C binding to distinct myosin binding sites, alone and in combination; 2) steps in the cross-bridge cycle affected by cMyBP-C binding to myosin S2; 3) the role of cMyBP-C phosphorylation in mediating contractile responses to padrenergic stimuli; and 4) whether expression of cMyBP-C N-terminal regulatory sequences is sufficient to induce cardiac hypertrophy in a dominant negative fashion. Results from the proposed experiments will provide new and relevant information regarding the function of MyBP-C, mechanisms of myosin regulation, and mechanisms by which mutations in the cMyBP-C cause human disease.
描述(由申请方提供):拟定实验的长期目标是了解肌球蛋白结合蛋白-C在心脏收缩调节中的功能。心肌肌球蛋白结合蛋白-C(cMyBPC)的突变几乎占所有遗传性肥厚型心肌病的一半,cMyBP-C在对正性肌力刺激的反应中被磷酸化,但cMyBP-C突变引起疾病的机制以及cMyBP-C在介导心脏收缩反应中的作用都没有得到很好的理解。到目前为止,解决MyBP-C功能的主要困难是无法系统地改变cMyBP-C含量或选择性地影响cMyBP-C磷酸化状态而不同时影响其他肌丝蛋白。然而,这两个技术限制将在所提出的实验中通过使用心脏中缺乏cMyBP-C的cMyBP-C敲除小鼠来克服。因此,cMyBP-C敲除小鼠提供了一个“空”背景,在此基础上测试cMyBP-C在健康和疾病中功能的特定机制假设。基于我们表征cMyBP-C敲除小鼠的初步研究,指导这些实验的工作假设是cMyBP-C通常起限制跨桥动力学和功率输出的作用,并且cMyBP-C的磷酸化解除这种抑制。我们进一步提出,cMyBP-C的收缩作用介导的结合肌球蛋白在两个不同的网站和cMyBP-C的结合引起的效果不同,这取决于是否一个或两个网站被占用。作为这一想法的推论,我们提出cMyBP-C N-末端与肌球蛋白S2的不受调节的结合,如可能发生在一些家族性肥厚性心肌病中,足以引起心肌病。这些假设将在四个特定目的中进行测试,这些特定目的旨在确定1)cMyBP-C与不同肌球蛋白结合位点结合(单独和组合)的收缩作用; 2)cMyBP-C与肌球蛋白S2结合影响的跨桥周期步骤; 3)cMyBP-C磷酸化在介导对肾上腺素能刺激的收缩反应中的作用;和4)cMyBP-C N-末端调节序列的表达是否足以以显性负性方式诱导心脏肥大。从拟议的实验结果将提供新的和相关的信息,MyBP-C的功能,肌球蛋白的调节机制,以及cMyBP-C突变导致人类疾病的机制。

项目成果

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Samantha P Harris其他文献

Samantha P Harris的其他文献

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{{ truncateString('Samantha P Harris', 18)}}的其他基金

Cut and paste of myosin binding protein-C in skeletal muscles
骨骼肌中肌球蛋白结合蛋白-C 的剪切和粘贴
  • 批准号:
    10571115
  • 财政年份:
    2023
  • 资助金额:
    $ 33.94万
  • 项目类别:
Molecular Mechanisms of Disease in a Novel Feline Model of Familial Hypertrophic
新型家族性肥厚型猫科动物模型中疾病的分子机制
  • 批准号:
    8111960
  • 财政年份:
    2010
  • 资助金额:
    $ 33.94万
  • 项目类别:
Molecular Mechanisms of Disease in a Novel Feline Model of Familial Hypertrophic
新型家族性肥厚型猫科动物模型中疾病的分子机制
  • 批准号:
    7990837
  • 财政年份:
    2010
  • 资助金额:
    $ 33.94万
  • 项目类别:
cMyBPC and Regulation of Myocardial Contraction
cMyBPC 和心肌收缩的调节
  • 批准号:
    7839733
  • 财政年份:
    2009
  • 资助金额:
    $ 33.94万
  • 项目类别:
cMyBPC and Regulation of Myocardial Contraction
cMyBPC 和心肌收缩的调节
  • 批准号:
    7560160
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction
心肌肌球蛋白结合蛋白-C 在心肌收缩调节中的作用
  • 批准号:
    10155578
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
cMyBPC and Regulation of Myocardial Contraction
cMyBPC 和心肌收缩的调节
  • 批准号:
    7277287
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
Role of Myosin Binding Protein-C in the Regulation of Myocardial Contraction
肌球蛋白结合蛋白-C 在心肌收缩调节中的作用
  • 批准号:
    8239000
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
Role of Myosin Binding Protein-C in the Regulation of Myocardial Contraction
肌球蛋白结合蛋白-C 在心肌收缩调节中的作用
  • 批准号:
    8604170
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
Role of Myosin Binding Protein-C in the Regulation of Myocardial Contraction
肌球蛋白结合蛋白-C 在心肌收缩调节中的作用
  • 批准号:
    8792856
  • 财政年份:
    2005
  • 资助金额:
    $ 33.94万
  • 项目类别:
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