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Regulation of atrial contractility in cardiomyopathy

心肌病心房收缩力的调节

基本信息

批准号：
10687398
负责人：
David Y Barefield
金额：
$ 59.67万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687398
关键词：
Actomyosin Adult Affect Arrhythmia Atrial Fibrillation Atrial Function Binding Binding Proteins Binding Sites C-terminal Cardiac Myocytes Cardiac Myosins Cardiomyopathies Cells Competitive Binding Data Data Set Development Diastole Dilated Cardiomyopathy Disease Equilibrium Exhibits Functional disorder Gene Expression Profile Genes Genetic Head Heart Heart Atrium Heart Diseases Heart failure Human Hypertrophic Cardiomyopathy Impairment Kinetics Lead Left Ventricular Function Life Link LoxP-flanked allele Measurement Medial Mediating Microfilaments Missense Mutation Modeling Mus Mutation Myocardial dysfunction Myofibrils Myopathy Myosin ATPase Myosin S-1 Neonatal Pathogenicity Pathologic Pattern Prognosis Property Proteins Rattus Regulation Relaxation Research Risk Role Sampling Sarcomeres Signal Pathway Sinus Site Thick Filament Thin Filament Variant Ventricular X ray diffraction analysis cardiac tissue engineering comorbidity differential expression heart function induced pluripotent stem cell derived cardiomyocytes link protein mouse model myosin-binding protein C promoter stoichiometry variant of unknown significance

项目摘要

PROJECT SUMMARY Cardiomyopathies are a group of diseases, commonly with genetic causes, that impairs cardiac function and can lead to heart failure. The focus of cardiomyopathy research has been left ventricular function, as this chamber is critical for supporting life, but the whole heart is typically affected by these diseases. The cardiac atria provide many functional roles in regulating cardiac function and have a gene expression profile that allows them to fulfil their specific function. We provided evidence that mutations in myosin binding protein H-like (MyBP-HL), a protein that is specifically expressed in the atria, is linked with dilated cardiomyopathy and arrhythmias in humans and mice. This protein is highly related to the carboxy terminal domains of the well- studied protein cardiac myosin binding protein-C (cMyBP-C), dysfunction in which is highly associated with the development of cardiomyopathy. We identified that both these proteins compete for a discrete number of myosin binding sites and maintain a ~1:1 ratio in human and mouse atria. We hypothesize that missense mutations in the myosin binding domains of these two proteins disrupts stoichiometry of these proteins and leads to atrial myopathy and overall cardiac dysfunction. We propose to model these mutations in human induced pluripotent stem cell derived cardiomyocytes and assess the effect of binding on the stoichiometry of these two proteins. We will use these cells to model different levels of each myosin binding protein and generate engineered heart tissue that we will assess for alterations in contractile kinetics.

项目总结