The cardiac jelly matrix separating the myocardium and endocardium of the primitive heart forms endocardial I cushions through regional expansion in the atrioventricular canal (AV canal) and outflow tract. A specified population of endocardial cells execute an epithelial to mesenchymal cell transformation (EMT) creating mesenchymal cells that invade the cushion matrix to form cardiac valves and complete chamber septation. Improper heart valve development is responsible for a significant proportion of congenital heart defects diagnosed during infancy and an unknown yet speculated large contribution to valve disease in adults. Previous studies have shown that hyaluronan (HA) as produced by HA-synthase 2 (Has2) is required for the regional cushion expansion creating an environment for EMT. The presence of HA coincides and appears to promote the production of cushion mesenchyme concomitant with erbB2 and erbB3 receptor phosphorylation. Despite these critical observations into the structural role of extracelluar HA in cushion formation, the mechanisms regulating Has2 dependent HA production and HA bioactivity during cardiac cushion mesenchyme production are not known. Furthermore, the regulation of Has2 expression during heart valve development has not been explored. We hypothesize that Has2 and HA production is dynamically regulated by erbB ligands and cognate receptor tyrosine kinases; and HA reciprocally potentiates erbB2/erbB3 activation as required for cushion EMT. This proposal will investigate Has2 and the ErbB receptors in mammalian cardiac cushion development and assess their functional integration by using mouse models of endocardial cushion and valve morphogenesis. These studies are expected to provide imperative knowledge into the molecular mechanisms of early heart valve development, which can be used for translational studies directed at novel repair strategies including valve regeneration. ? ?
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