Role of Endothelial SOX17 Deficiency in the Pathogenesis of Pulmonary Hypertension

项目摘要 肺动脉高压（pulmonary hypertension，PH）是一种以肺血管阻力进行性增加为特征的疾病 和闭塞性肺血管重塑，导致右心肥大、衰竭和过早死亡。 死亡血管重塑和闭塞性血管病变形成的潜在机制仍然存在 不清楚特发性肺动脉高压患者存在基因突变和变异 (PAH)和PAH伴先天性心脏病。然而，内皮SOX 17在调节细胞凋亡中的机制作用， 肺血管重构在PH发病机制中的作用尚未见报道。我们假设内皮细胞 S0X17缺陷导致E2F1信号传导的激活，这有助于内皮细胞过度增殖和 我们将1）确定内皮SOX 17在PH发病机制中的新作用， 使用多种转基因小鼠和大鼠模型研究PH的发病机制。2)描述分子机制 内皮SOX 17缺陷下游介导肺血管重塑和PH和3）探索 靶向E2F1信号传导的翻译潜力。完成我们提出的研究将提供一个新的 有效治疗PH患者的治疗策略。

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.