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
- 来源:
- 关键词:actinsasymmetric septal hypertrophybeta adrenergic receptorbinding proteinsbinding sitesbiomechanicscalcium fluxdisease /disorder modelenzyme activitygene expressiongene mutationgenetic disordergenetically modified animalsheart contractionhypertrophic myocardiopathylaboratory mouselaboratory rabbitmicrofilamentsmuscle cellsmyosinsphosphorylationprotein Cprotein kinase Aprotein structure functionsite directed mutagenesistroponin
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(由申请人提供):拟议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)突变占所有遗传性肥厚性心肌病病例的近一半,cMyBP-C在肌张力刺激下被磷酸化,但cMyBP-C突变导致疾病的机制以及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,这些技术上的限制将在拟议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敲除小鼠为测试cMyBP-C在健康和疾病中功能的特定机制假设提供了“零”背景。根据我们对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通常会限制过桥动力学和功率输出,而cMyBP-C的磷酸化会减轻这种抑制。我们进一步提出,cMyBP-C的收缩作用是通过在两个不同的位点与肌球蛋白结合介导的,cMyBP-C结合所引起的效果取决于是否占据一个位点或两个位点。作为这一观点的推论,我们提出cMyBP-C n端与肌球蛋白S2的不调节结合,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标中进行测试,旨在确定1)cMyBP-C与不同肌球蛋白结合位点的收缩效应,单独或联合;2)受cMyBP-C与肌球蛋白S2结合影响的跨桥周期的步骤;3) cMyBP-C磷酸化在介导神经刺激收缩反应中的作用;4) cMyBP-C n端调控序列的表达是否足以以显性阴性方式诱导心肌肥厚。这些实验的结果将为MyBP-C的功能、肌球蛋白调控机制以及cMyBP-C突变导致人类疾病的机制提供新的相关信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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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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