Congenital Heart Disease is the most common congenital anomaly in newborn babies, accounting for one third of all major congenital anomalies. Despite recent congenital heart disease genetic studies highlighting the critical role of cardiac transcriptional and chromatin regulators during heart development, our understanding of how these developmental regulators interact to create the dynamic gene regulatory networks that mediate heart development remains to be fully elucidated. Thus, we propose to define and assay the cardiovascular developmental regulators and their gene regulatory networks that direct the development of the vast array of cardiovascular cell types creating the mammalian heart. To achieve this goal, a multi-disciplinary experimental and computational systems biology approach will be implemented to: (1) elucidate gene regulatory networks that establish the cardiogenic cellular hierarchy of the developing mammalian heart, (2) investigate the spatiotemporal organization of the cardiogenic cellular hierarchy during mouse embryogenesis and heart morphogenesis and (3) functionally examine how distinct cardiovascular developmental sources create specific cardiovascular lineages contributing to the developing heart.
This proposal seeks to illuminate the cardiogenic cellular hierarchy and the gene regulatory networks that determine the origins and fates of distinct cardiovascular progenitor cells during heart development. Results from these studies will yield new insights into how disrupted cardiovascular regulatory networks lead to congenital heart disease and how they may be modified to develop treatments to improve patient outcome.
