慢性血栓栓塞性肺动脉高压（CTEPH）致残率和病死率高。纤维蛋白（Fb）、组织因子（TF）及肺动脉内皮细胞（PAEC）自噬改变可致内皮功能障碍。转录因子FoxO1是调控细胞自噬的关键点，但其对Fb/TF介导的CTEPH内皮重塑和功能障碍中自噬的作用及机制未明。我们前期研究表明FoxO1在CTEPH鼠模型中表达随着栓塞时间延长下调更明显。本研究拟通过CTEPH患者临床标本与CTEPH动物模型结合，离体及在体实验特异性阻断FoxO1上游Fb/TF-MAPK通路、FoxO1基因敲除、FoxO1抑制剂及激动剂等方面探讨FoxO1调控CTEPH中PAEC自噬和功能的作用；通过PCR阵列技术及RFP-GFP-LC3B等方法分析PAEC自噬情况，观察PAEC形态及功能改变；再通过应用FoxO1基因的组成型活化突变体进行干预，期望能改善肺血管重塑，为早期干预、防治CTEPH的发生发展提供新的思路和方法。

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with high disability and mortality. Endothelial dysfunction can be caused by fibrin (Fb) and tissue factor (TF), as well as autophagy changes of pulmonary artery endothelial cell (PAEC). Forkhead box transcription factor O-1 (FoxO1) plays a key role in regulating cellular autophagy, however, its effect and mechanisms on PAEC autophagy remain unclear during CTEPH vascular endothelium remodeling induced by Fb and TF. Our preliminary studies have showed that the expression of FoxO1 can be significantly down-regulated along with the duration of embolization in the rat model of CTEPH. To explore the effect and mechanisms of FoxO1 on regulating cell autophagy and dysfunction of PAEC in CTEPH, the clinical specimens of patients and animal models with CTEPH will be combined to be used in this study. The role of FoxO1 will be explored by specifically blocking the upstream Fb/TF-MAPK pathway, knocking out FoxO1 gene,using the FoxO1 inhibitors as well as agonists in vitro and in vivo experiments. The autophagy of PAEC will be also analyzed by the methods of PCR array and RFP-GFP-LC3B kits and the morphological and functional changes of the PAECs will be observed. Furthermore, the constitutively active mutant of FoxO1 Ad-Foxo1: AAA will be selectively delivered into the lungs of rats to investigate if it can improve the pulmonary artery vascular endothelium remodeling. It can be expected that the constitutively active mutant of FoxO1 may offer a potential therapeutic option for CTEPH vascular remodeling.