Many of the biological programs that coordinate homeostasis of the valves have their origins in embryonic development. As the tissue matures, these programs abate to a quiescent mode that is poorly understood. During disease pathogenesis, these same molecules and cellular decisions are markedly reactivated, but this time instead of restoring tissue health promote pathogenic remodeling towards fibrosis and calcification. A cardinal example we have focused on is the reactivation of endothelial to mesenchymal transformation in diseased heart valves. We have developed unique in vitro test environments to quantify and profile the phenotypes of endothelium that transform and those that remain quiescent. We have discovered that transformed endothelium is a uniquely calcifying progenitor. We are now identifying novel signaling mediators of these processes, including inflammatory and oxidative stress molecules. We also have identified unique roles for mechanobiological signaling through adhesion proteins. We are testing how small molecule manipulation of these developmentally informed biological programs restore homeostatic VEC-VIC interactions, first in vitro and then in vivo. If successful, we will initiate human trials with these druggable targets with our clinical collaborators. As we identify novel mediators of adult valve homeostasis and calcific degeneration, we will then test for previously unknown roles in embryonic valve formation and maturation. For new mechanisms we identify, we will then explore whether targeted molecular compounds manipulating these shared molecular programs can help reduce malformation severity.