Saturday, October 12, 2024
10/12/2024
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.
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