Regulation of atrial contractility in cardiomyopathy

心肌病心房收缩力的调节

• 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
• 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

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 心肌病是一组疾病，通常是由遗传原因引起的，它损害心脏功能和 会导致心力衰竭。心肌病研究的重点一直是左心功能，因为 心腔对维持生命至关重要，但整个心脏通常会受到这些疾病的影响。心脏 Atria在调节心脏功能方面提供了许多功能，并且有一个基因表达谱，可以 他们必须履行自己的特定职能。我们提供的证据表明，肌球蛋白结合蛋白H-like突变 (MyBP-HL)是一种在心房特异表达的蛋白质，与扩张型心肌病和 人类和小鼠的心律失常。该蛋白与井的羧基末端结构域高度相关- 研究了心肌肌球蛋白结合蛋白-C(cMyBP-C)，其功能障碍与 心肌病的发展。我们发现这两种蛋白质都竞争不同数量的 在人和小鼠的心房中，肌球蛋白结合位点数和肌球蛋白结合位点数维持在~1：1的比例。我们假设这是错误的 这两种蛋白质肌球蛋白结合区的突变会破坏这些蛋白质的化学计量比 会导致心房肌病和整体心脏功能障碍。我们建议在人类身上模拟这些突变 诱导多能干细胞来源的心肌细胞，并评估结合对心肌细胞化学计量的影响 这两种蛋白质。我们将使用这些细胞来模拟不同水平的肌球蛋白结合蛋白和 产生工程化的心脏组织，我们将评估收缩动力学的变化。