Systems Pharmacology Approaches Identify Drugs and Mechanisms That Regulate Cardiomyocyte Growth

Cardiomyocyte growth is essential for development and in response to increased
demand, but physiological stressors can trigger pathological growth. In fetal hearts, cardiomyocytes are capable of regenerative growth, where proliferating cardiomyocytes replenish dead cells. In mature hearts growth is characterized almost entirely by hypertrophy, which typically leads to cardiac disease such as heart failure. Understanding what regulates cardiomyocyte growth is challenging due to the complexity of intracellular signaling, making therapeutic strategies difficult to determine. The goal of this dissertation is to develop and apply systems biology methods to identify drugs and mechanisms that regulate cardiomyocyte hypertrophy and proliferation. First, I perform a virtual drug screen to predict drugs that inhibit hypertrophy. Second, I develop a novel method, LogiRx, to predict the mechanistic behavior of drugs from an experimental screen. Third, I develop and use a model of TGFβ-regulated proliferation to test multiple mechanistic hypotheses. Through this work, I identify novel drug applications and key mechanistic regulators of cardiomyocyte growth.