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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. !

摘要