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

基本信息

批准号：
8604170
负责人：
Samantha P Harris
金额：
$ 36.44万
依托单位：
UNIVERSITY OF ARIZONA
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604170
关键词：
Actins Actomyosin Adolescent Affect Alanine Algorithms Award Binding Boxing Cardiac Cardiac Myosins Clinical Conserved Sequence DAG/PE-Binding Domain Data Devices Disease Goals Grant Head Health Heart Heart failure Human Hypertrophic Cardiomyopathy In Vitro Incidence Kinetics Ligand Binding Ligands Maps Mechanics Mediating Missense Mutation Molecular Muscle Muscle Contraction Mutation Myocardial Contraction Myocardium Myosin ATPase N-terminal Older Population Oranges Peptides Phosphorylation Positioning Attribute Proline Property Protein Isoforms Proteins Recombinants Regulation Role Sarcomeres Serine Speed Structure Testing Thick Filament Thin Filament Transgenic Mice Transgenic Organisms Troponin I Work alanylproline base disease diagnosis disease-causing mutation hemodynamics improved in vivo insight molecular recognition myosin-binding protein C novel outcome forecast protein protein interaction research study single molecule sudden cardiac death

项目摘要

ABSTRACT The long-range goal of the proposed experiments is to understand the function of cardiac myosin binding protein-C (cMyBP-C) in the regulation of myocardial contraction. Mutations in cMyBP-C cause hypertrophic cardiomyopathy and heart failure in millions of people worldwide and under normal conditions cMyBP-C regulates contraction on a beat-to- beat basis. However, neither the mechanisms by which cMyBP-C mutations cause disease nor the mechanisms by which cMyBP-C affects contraction are completely understood. Until now the prevailing hypothesis has been that MyBP-C reversibly limits the speed of contraction by binding to myosin and restricting the ability of myosin heads to extend away from thick filaments and to undergo cycles of interaction with actin on the thin filaments. However, discoveries made by our lab during the first period of this grant challenged this idea and suggest that cMyBP-C itself can bind to actin or other ligands to influence contraction. Aims here will test the role of ligand binding interactions mediated by cMyBP-C by probing the functional significance of novel Molecular Recognition Features (MoRFs) in the regulatory M- domain of cMyBP-C that confer specific binding of the cMyBP-C N-terminus to actin or that mediate other functional effects of the N-terminus in vitro. Understanding the function of the MoRF segment will further provide new insights into disease since HCM missense mutations are clustered within this segment. Specific Aims will 1) map residues in the M-domain MoRFs that mediate actin binding and other functional effects of the M-domain in vitro and in vivo using novel transgenic mice; 2) determine whether the proline-alanine and C1 domains of cMyBP-C outside the M-domain contribute the function of cMyBP-C in vivo using new and existing transgenic mice; and 3) define structural interactions of cMyBP-C with thin and thick filaments. Results from the proposed experiments will provide new insights into the function of MyBP-C and regulatory mechanisms of myocardial contraction in health and disease. !

抽象的提出的实验的远程目标是了解心肌收缩调节中心脏肌球蛋白结合蛋白-C（CMYBP-C）。 CMYBP-C的突变会导致肥厚性心肌病和心力衰竭数百万 CMYBP-C在全球范围内且在正常条件下调节节拍的收缩击败基础。但是，CMYBP-C突变引起疾病的机制也不完全了解CMYBP-C影响收缩的机制。到目前为止普遍的假设是MYBP-C可逆地限制了收缩速度与肌球蛋白结合并限制肌球蛋白头从厚厚细丝并在细丝上与肌动蛋白的相互作用进行循环。然而，我们实验室在这笔赠款的第一阶段中提出的发现挑战了这一想法和建议CMYBP-C本身可以与肌动蛋白或其他配体结合以影响收缩。目标这里将通过探测由CMYBP-C介导的配体结合相互作用的作用调节M-中新型分子识别特征（MORF）的功能意义 CMYBP-C的域，赋予CMYBP-C N末端对肌动蛋白的特定结合或介导N端在体外的其他功能效应。了解由于HCM错义突变，MORF细分市场将进一步提供有关疾病的新见解聚集在此细分市场中。具体目的将1）M型膜中的残留物映射残基介导M-域在体外和体内的肌动蛋白结合和其他功能效应使用新型的转基因小鼠； 2）确定脯氨酸 - 丙氨酸和C1域是否 M域外部的CMYBP-C使用新的和现有的转基因小鼠； 3）定义CMYBP-C的结构相互作用细丝。提出的实验的结果将为您的功能提供新的见解 MYBP-C和健康和疾病中心肌收缩的调节机制。呢