SPECIFIC REGULATION OF CARDIAC ATRIAL CONTRACTILITY
NHLBI - National Heart Lung and Blood Institute
About This Grant
PROJECT SUMMARY Cardiomyopathies are a group of diseases, commonly with genetic causes, that impair 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. The amino terminus of MyBP-HL is intrinsically disordered and highly unique. We observed that this N’-terminal 62 amino acid region can incorporate into the sarcomere and alter force generation and the myosin super-relaxed state. We will establish the physiological significance and define the mechanisms by which this amino terminal region regulates function. We identified that both MyBPs 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.
Focus Areas
Eligibility
How to Apply
Up to $644K
2030-06-30
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