Abstract
Introduction: Congenital heart defects (CHD) are a major cause of infant morbidity and the genetic nature of many CHD is still unknown. Because early heart development is highly conserved in humans, the zebrafish is a powerful model to rapidly identify putative CHD genes. It has been shown that hemodynamic forces generated by the circulatory system and detected by mechanosensors present in the endocardium act to drive cardiogenesis forward.Methods/Results: We identified the mechanosensitive ion channel Piezo1 as a regulator of outflow tract and aortic valve development in zebrafish and established that Piezo1 variants are associated with Bicuspid Aortic Valves (BAV) in humans. We will now build on these results and expand the cohort size substantially to determine the frequency and variance of Piezo1 mutations associated with BAV and other aortic CHD. We also propose to elucidate the molecular pathways controlled by Piezo1 and hemodynamic forces during heart development.Conclusion: By establishing Piezo1 as a major cause of CHD and by defining the molecular and cellular events of outflow tract and aortic valve development in normal and pathological conditions, we will deliver a reproducible benchmark that can be used by other researchers for validating factors that are associated with aortic CHD in humans.