Congenital heart disease (CHD) is the most common birth defect in humans, with patients having conotruncal defects comprising 30% of this population. Malformations in the distal ventricle, infundibulum, and proximal great arteries lead to conotruncal anomalies. Among these patients, a 17% mortality rate highlights the urgent need to better understand the early developmental cues that guide aberrations in outflow tract (OFT) morphogenesis.

Our goal is to uncover the molecular, cellular, and biomechanical mechanisms behind disruptions in OFT development that contribute to human conotruncal CHDs. We have identified Fibulin (Fbln) proteins as key regulators of the extracellular matrix (ECM) essential for OFT morphogenesis. Our research shows that Fblns are critical for establishing the proper size of the OFT, regulating smooth muscle cell addition, and modulating TGF-β signaling in late-differentiating progenitors that contribute to the arterial pole. By applying genetic, transcriptomic, cellular, and biomechanical techniques, we aim to understand how Fblns control ECM deposition and organization to shape the structural and functional properties of the cardiac OFT. Additionally, investigating the cell type-specific roles of Fbln proteins will help identify novel therapeutic targets and advance tissue engineering for OFT conduits and artificial valves.