Cardiomyopathy is tightly linked to heart failure, a condition that is associated with high morbidity and mortality. Mutations in sarcomeric genes are responsible for familial cardiomyopathy, including both dilated and hypertrophic cardiomyopathy. The genes encoding myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3) cause both dilated and hypertrophic cardiomyopathy. MYH7 mutations are mainly missense mutations falling within the motor and rod domains of myosin. In contrast to the missense mutations in MYH7, MYBPC3 mutations include a high percentage of frameshifting or truncating mutations, similar to those in the giant protein titin, encoded by TTN. In this application, I will study the role of myosin binding protein H-like (MyBP-HL) and its role in sarcomere function in normal and failed hearts. The observation that sarcomere mutations are responsible for inherited cardiomyopathy strongly suggests that other sarcomere proteins are similarly critical for the normal function of the heart. The central hypothesis of this proposal is that MyBP-HL plays a role in organizing and maintaining sarcomere structure in development and during adulthood, and truncating mutations or deletion results in aberrant function and the development of cardiomyopathy. In order to study this hypothesis, in Specific Aim 1, I will use induced pluripotent stem cell-derived cardiomyocytes taken from an individual carrying a truncating mutation MYBPHL. This mutation is linked to the development of cardiomyopathy in the proband and family members. I propose to develop a transgenic mouse expressing the truncating MYBPHL mutation, and through both the cells and mouse model I will study the expression and localization of the mutant protein and establish the physiological defects that occur due to its altered localization.
In Specific Aim 2, I will study a mouse carrying a MYBPHL-null mutation to evaluate the role MyBP-HL plays in the heart. The results from these aims will provide basic data to establish the physiological role of MyBP-HL and better our understanding of how mutations in the protein lead to disease. Overall, the objectives of this fellowship application are to provide the principal investigator with advanced training in genetic and cardiovascular biophysical techniques while elucidating the function of MyBP-HL in health and disease. The results from this study will provide new understanding of the pathogenesis of cardiomyopathy, and provide new targets to mitigate the course of disease. The basic science knowledge gained on the role of MyBP-HL will also inform the broader field of cardiovascular physiology and establish new lines of future inquiry.
This project is designed to understand the function of a new gene linked to human heart failure called myosin binding protein H-like. Myosin binding protein C is a protein critically important for heart function, and the proposed studies on the related protein myosin binding H-like will advance what is known about normal and failing hearts.
