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Current Projects
DEFINING THE MECHANISMS OF MYOSIN BINDING PROTEIN H-LIKE REGULATION OF ATRIAL SARCOMERE FUNCTION
Funded by the NIH (R01HL181346), this project aims to mechanistically define the roles of myosin binding protein H-like in regulating atrial contractility. MyBP-HL is a little understood protein that competes with cardiac myosin binding protein-C for atrial sarcomere incorporation (Barefield et al., 2023, PNAS). MyBP-HL has a novel unstructured amino terminal domain that we have discovered regulates sarcomere contractile function.
CONTRACTILE FUNCTION OF VENTRICULAR CONDUCTION SYSTEM CARDIOMYOCYTES
Funded by the American Heart Association's Innovative Project Award (25IPA1454587), this project seeks to answer a basic question about ventricular conduction system cardiomyocytes: does their contractile function actually matter?
The ventricular conduction system is made of cardiomyocytes that have been highly specialized to conduct electrical impulses rapidly throughout the ventricle. It has long been known that these cells do contain contractile structures (sarcomeres), but their actual contractile properties have never been studied. We aim to: 1) determine the contractile proteome of the ventricular conduction system and establish their contractile parameters; 2) test whether cardiomyopathy-causing mutations in sarcomere proteins can alter the morphology and function of the conduction system and its calcium handling; 3) establish whether contractile function matters in the conduction system by arresting contractile function specifically in the conduction system.
DIFFERENTIAL REGULATION OF ATRIAL AND VENTRICULAR CONTRACTILE FUNCTION
Atrial and ventricular cardiomyocytes have differential expression and regulation of sarcomere proteins. New therapeutic myosin modulators have been studied primarily in ventricular cardiomyocytes. However, their effects in the atria remain unknown. Our lab aims to investigate differences in atrial and ventricular cardiomyocyte contraction and how modulators of contraction, including β-adrenergic signaling and myosin modulators, differentially regulate contraction in atrial cardiomyocytes. We are utilizing several in-vitro cardiomyocyte models including iPSC-derived cardiomyocytes, neonatal rat cardiomyocytes, and isolated adult guinea pig cardiomyocytes to investigate these questions.
ATRIAL CONTRACTION AND PROTEOLYTIC DEGRADATION IN ATRIAL FIBRILLATION
Atrial Fibrillation is the most common cardiac rhythm disturbance worldwide and is characterized by irregular electrical conduction in the atria. Because atrial fibrillation is primarily an electrical disease, treatments often include a restoration of the natural electrical rhythm. After this restoration, patients often experience a period of depressed atrial contraction known as atrial stunning. The phenomenon of atrial stunning led to the hypothesis that atrial cardiomyocytes experience contractile remodeling during AFib. Our previous study found that there is widespread myofilament degradation that was linked to increased calpain activity and depressed contractile function in AFib atrial cardiomyocytes (Cizauskas et. al. 2024, AJP Heart). Current studies are focused on investigating calpain as the main driver of depressed contractile function in AFib, investigating the effect of calpain-mediated degradation of specific myofilament proteins in AFib, and understanding the role of sarcomere recovery in atrial stunning. We are working on establishing an iPSC-derived atrial cardiomyocyte model of tachypace-induced AFib as well as utilizing mouse models of AFib to parse out these mechanisms.
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