SphK1/S1P信号通路介导肺动脉平滑肌细胞增殖的分子机制研究

新近的研究提示SphK1/S1P信号通路介导肺血管重塑的发生，但目前仍不清楚上调肺动脉平滑肌细胞中SphK1表达及S1P诱导肺动脉平滑肌细胞增殖的分子信号机制。本研究将探讨：（1）PDGF是否可上调肺动脉平滑肌细胞中SphK1表达，增加S1P产生；激活何种信号通路（Akt 或ERK）介导PDGF诱导的SphK1表达；（2）S1P是否通过S1P受体激活与之偶联的STAT3信号通路，进而调控Skp2/p27轴，诱导肺动脉平滑肌细胞增殖；（3）干预SphK1/S1P信号通路可否抑制动物模型中肺动脉平滑肌细胞增殖及肺血管重塑，预防及治疗肺动脉高压，其机制是否与抑制STAT3调控的Skp2/p27变化相关。本研究将从培养的肺动脉平滑肌细胞及肺动脉高压动物模型两个方面探索SphK1/S1P信号通路在肺动脉平滑肌细胞增殖中的作用及机制，本研究将为肺动脉高压的治疗提供新的理论基础、实验依据及治疗靶点。

Recent studies have indicated that SphK1/S1P signaling pathway is involved in the development of pulmonary vascular remodeling, while the molecular mechanisms responsible for up-regulation of SphK1 expression in pulmonary arterial smooth muscle cell and S1P-inducing pulmonary arterial smooth muscle cell proliferation are still unclear. The aims of the present proposal will explore: (1) whether PDGF up-regulates SphK1 expression and increases S1P production in pulmonary arterial smooth muscle cell, and whether activation of Akt or ERK1/2 signaling mediates PDGF-induced SphK1 expression; (2) whether S1P binds to specific S1P receptor and further activates STAT3 cascades，which in turn modulates Skp2/p27 axis leading to pulmonary arterial smooth muscle cell proliferation;(3) whether intervention of SphK1/S1P pathway in animal model of pulmonary arterial hypertension inhibits pulmonary arterial smooth muscle cell proliferation and pulmonary arterial remodeling, and therefore prevent and treat the development of pulmonary arterial hypertension, and whether this mechanism is associated with the suppression of STAT3 regulation of Skp2/p27 axis. The present study will address the role and mechanisms of SphK1/S1P signaling in the proliferation of pulmonary arterial smooth muscle cell in cultured pulmonary arterial smooth muscle cell and animal model of pulmonary arterial hypertension, our study will provide novel theoretical evidences and new targets for the treatment of pulmonary arterial hypertension.