A Comprehensive Systems Biology Approach to Identify Novel Mechanisms Regulating Cardiomyocyte Proliferation

Heart disease is the leading cause of death among men, women, and people of most racial and ethnic groups in the US. Myocardial infarction and other cardiomyopathies lead to heart failure and cause irreversible loss of cardiac muscle due to the limited regenerative capacity of adult mammalian hearts. Current cardiovascular studies elucidate cardiomyocyte proliferation as a potential therapeutic strategy. The overreaching goal of this dissertation is to predict and identify novel mechanisms that regulate cardiomyocyte proliferation. In Aim 1, I developed a computational model of the cardiomyocyte proliferation signaling network to elucidate key pathways regulating proliferation. In Aim 2, I created a pipeline that identifies prominent cell cycle phases within single-cell data and predicts transition rates between cell cycle phases. Aim 3 explores post-transcription regulation of cardiomyocyte proliferation using network modeling. Thus, this work provides an innovative framework for understanding the dynamics of cardiomyocyte proliferation through signaling pathways and the cell cycle.