Regulation of atrial contractility in cardiomyopathy

项目摘要 心肌病是一组疾病，通常具有遗传原因，损害心脏功能， 会导致心力衰竭心肌病研究的重点一直是左心室功能，因为这 心室对于维持生命至关重要，但整个心脏通常会受到这些疾病的影响。心脏 心房在调节心脏功能中提供许多功能作用，并且具有允许 以履行其特定职能。我们提供了肌球蛋白结合蛋白H样突变的证据， MyBP-HL是一种在心房中特异性表达的蛋白质，与扩张型心肌病有关， 人类和小鼠的心律失常。这种蛋白质是高度相关的羧基末端结构域的井- 研究了蛋白质心肌肌球蛋白结合蛋白-C（cMyBP-C），其中功能障碍与 心肌病的发展。我们发现，这两种蛋白质竞争一个离散的数量， 肌球蛋白结合位点，并在人和小鼠心房中保持约1：1的比例。我们假设这种误解 这两种蛋白质的肌球蛋白结合结构域中的突变破坏了这些蛋白质的化学计量， 导致心房肌病和整体心脏功能障碍。我们建议在人类中模拟这些突变 诱导的多能干细胞衍生的心肌细胞，并评估结合对诱导的多能干细胞衍生的心肌细胞的化学计量的影响。 这两种蛋白质。我们将使用这些细胞来模拟每种肌球蛋白结合蛋白的不同水平， 产生工程心脏组织，我们将评估收缩动力学的改变。

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.