The goal of the proposed work is to determine if melusin acts as a cardiac-specific mechanotransducer in human cardiomyocytes leading to hypertrophy, and unravel the mechanisms leading to activation of this pathway. Myocardial tissue responds to elevated hemodynamic load by hypertrophic growth to increase wall thickness and thereby reduce wall stress. How these loads are transduced by individual cardiomyocytes in the heart is not well understood, but melusin (ITGB1BP2), a ?1 integrin binding protein, may play an important role. Melusin forms a signalosome at the costameres of cardiomyocytes and sits at a nexus between two major hypertrophic pathways, ERK and AKT. We hypothesize that it has an autoinhibitory state due to intramolecular interactions that hinder its effect in hypertrophic signaling, but this autoinhibition may be attenuated in response to tension.
The specific aims of this proposal will test the effects of melusin on pathological and physiological hypertrophy in transgenic mice, conduct controllable mechanistic studies in human engineered heart tissue, and examine whether intramolecular interactions inhibit its assembly at adhesion sites. These studies will elucidate if melusin plays a role in tension-mediated hypertrophy and verify its response in a human cardiac organoid model and with bioengineering approaches using human induced pluripotent stem cell derived cardiomyocytes. The health impact of this work will identify whether melusin is a key player in hypertrophy and provide a detailed understanding on how melusin affects cardiac growth in response to inherited cardiomyopathies and hemodynamic overload.
Cardiac hypertrophy is associated with increased cardiovascular risk and can arise from inherited mutations or hypertensive conditions. The goal of this project is to understand the mechanisms of mechanotransduction by melusin, a cardiac-specific protein, and in doing so, identify strategies that can lessen the risk of heart failure by counteracting inherited cardiomyopathies and tension-mediated hypertrophy.