Regulation of endocardial cell plasticity during embryonic heart valve development and maturation through BMP SMAD

Congenital heart diseases (CHDs) are the most common birth defects, with nearly a third involving heart valve defects. During the last decade, it has become increasingly clear that the Bone Morphogenetic Protein (BMP) and Notch-mediated signaling cascades are both key regulators of embryonic and postnatal heart valve development as well as adult valve pathogenesis. Disruption of their signaling has been linked to valve defects in animal models and humans. Although well described in their separate roles during early heart valve development, little is known about their crosstalk during embryonic and postnatal valve development. The lab recently showed a critical BMP-Notch cross-talk mechanism during blood vessel formation. Here, I will investigate how BMP-SMAD mediated signaling affects Notch-mediated signaling and what the implication is on developing atrioventricular cushions (AVC) and the maturing postnatal valves. This project will integrate the use of genetic mouse models, ex vivo analysis of living tissues and gain and loss-of-function experiments to better understand the molecular regulations behind normal heart valve development. Ultimately, this type of research may impact investigations on congenital and acquired valve diseases, and lead to an improvement in clinical interventions.