PROJECT SUMMARY
Pulmonary hypertension (PH) is characterized by progressive increase of pulmonary vascular resistance
and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature
death. The underlying mechanisms of vascular remodeling and obliterative vascular lesion formation remain
unclear. Genetic mutations and variants were found in patients with idiopathic pulmonary arterial hypertension
(PAH) and PAH with congenital heart disease. However, the mechanistic role of endothelial SOX17 in regulating
pulmonary vascular remodeling in the pathogenesis of PH has not been reported. We hypothesis that endothelial
SOX17 deficiency leading to activation of E2F1 signaling which contributes to endothelial hyperproliferation and
anti-apoptosis in the pathogenesis of PH. We will 1) define the novel role of endothelial SOX17 in the
pathogenesis of PH using multiple transgenic mouse and rat models. 2) delineate the molecular mechanisms
downstream of endothelial SOX17 deficiency in mediating pulmonary vascular remodeling and PH and 3) explore
the translational potential of targeting E2F1 signaling. Completing our proposed study will provide a novel
therapeutic strategy for the effective treatment of PH in patients.