Hemodynamic Flow-Mediated Myocardial Reprogramming Impacts Cardiac Development

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PROJECT SUMMARY Cardiac morphogenesis is a complex process that is mediated by not only cellular, molecular and genetic factors but also environmental influences, such as hemodynamic flow. Disruption in these developmental events can result in Congenital Heart Disease (CHD), the most common birth defect in humans, which affects nearly one out of every one-hundred live births and is responsible for the vast majority of prenatal losses. Although several cardiac gene regulatory programs are known to play an important role in cardiac development, specific disease-causing genes so far account for only ~10% of patients with CHD, suggesting that additional genetic and environmental etiologies, including biophysical forces, may contribute toward this disease. Thus, illuminating the cellular, molecular, and physiologic basis of how biophysical factors influence cardiac morphogenesis may provide novel insights into the prevention, diagnosis, and treatment of patients predisposed for CHD. Although recent studies have shown that biomechanical forces such as cardiomyocyte contractility and intracardiac hemodynamic flow may regulate cardiac morphogenesis, the underlying mechanisms of how these biophysical forces specifically contribute to various aspects of cardiac development remains to be elucidated. Here, we propose that alterations in hemodynamic forces may impact cardiomyocyte cell identity through an “adaptive cellular reprogramming” process where cardiomyocytes that retain sufficient cellular plasticity are able to reprogram in order to change their cell fate in response to environmental influences. Thus, the overall goals of these proposed studies are to illuminate how the heart senses biomechanical forces and transduces their signal to control cardiomyocyte reprogramming. The results of these studies will not only elucidate how hemodynamic forces may adaptively alter cardiomyocyte fate during heart development to guide cardiac morphogenesis but also provide insight into how the heart may reprogram cardiomyocytes in response to perturbations in hemodynamic flow due to structural or functional heart defects. !