新近的研究发现，YAP蛋白功能增强促进肺动脉平滑肌细胞增殖，参与肺血管重塑发生，但调控YAP的上游分子机制及下游的关键靶点目前尚不完全清楚。本研究将探索：（1）S1P是否通过激活RhoA/ROCK信号通路去除YAP磷酸化，促进YAP蛋白细胞核移位；（2）S1P是否通过激活STAT3信号通路，上调miRNA-135b，进而下调 βTrCP蛋白表达，抑制UPS介导的YAP蛋白降解，增加YAP蛋白水平；（3）YAP蛋白功能增强是否通过上调miRNA-130表达，抑制BMPR2表达，进而下调Id蛋白水平，上述miRNA-130/BMPR2/Id轴序列性变化是否介导了S1P通过诱导YAP促进肺动脉平滑肌细胞增殖的作用。我们将以原代培养的肺动脉平滑肌细胞及缺氧或野百合碱诱导的肺动脉高压动物模型为研究对象，采用分子生物学的实验技术和方法验证我们的科学假设，为肺动脉高压的临床治疗提供理论基础及实验基础。

Recent studies indicate that YAP promotes the proliferation of pulmonary arterial smooth muscle cells and therefore the development of pulmonary vascular remodeling, yet the upstream regulation mechanisms and downstream targets of YAP are still unclear. The aims of the present study are to explore: (1) whether S1P activates RhoA/ROCK signaling pathway and then de-phosphorylates YAP and promotes YAP nuclear translocation; (2) whether S1P activates STAT3 signaling pathway and then up-regulates miRNA-135b, this further down-regulates βTrCP and inhibits UPS-mediated YAP degradation to increase YAP protein level; (3) whether activation of YAP up-regulates miRNA-130, and then inhibits BMPR2 expression which further reduces Id protein level, these changes mediate S1P-induced YAP stimulation of pulmonary arterial smooth muscle cell proliferation. We will test these hypothesis in primary cultured pulmonary arterial smooth muscle cells and rats model of pulmonary arterial hypertension induced by hypoxia or monocrotalin using methods of molecular biology. Our study will provide theoretical and experimental basis for the prevention and treatment of pulmonary arterial hypertension in clinic.