NIH Reporter #5R01HL181346-02

SPECIFIC REGULATION OF CARDIAC ATRIAL CONTRACTILITY

This award funds research on the regulation of cardiac atrial contractility, focusing on the role of MyBP-HL protein mutations linked to cardiomyopathy and arrhythmias. The project will study the physiological impact of these mutations and model them in stem cell-derived cardiomyocytes to understand their effects on heart function.

Description

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 fulfill their specific function. Evidence suggests mutations in myosin binding protein H-like (MyBP-HL), a protein specifically expressed in the atria, are linked with dilated cardiomyopathy and arrhythmias in humans and mice. This protein is related to the carboxy terminal domains of cardiac myosin binding protein-C (cMyBP-C), dysfunction in which is associated with cardiomyopathy. The N-terminal region of MyBP-HL can incorporate into the sarcomere, altering force generation and the myosin super-relaxed state. The project aims to establish the physiological significance of this region, investigate how mutations disrupt protein stoichiometry, and model these mutations in human induced pluripotent stem cell-derived cardiomyocytes to assess effects on contractile kinetics.

View original record