STAT4/Epac1信号介导的线粒体代谢功能障碍在睡眠呼吸暂停相关肺血管重构中的作用及机制研究

慢性间歇低氧（CIH）是睡眠呼吸暂停综合征（SAS）最主要的病生表现，与持续低氧诱导肺动脉高压（PH）机制不同，CIH诱导PH的具体病理机制尚不明确，CIH可诱导肺血管重构，阻断CIH相关肺血管重构有望特异性干预SAS相关PH的发生发展过程。我们预实验结果发现cAMP蛋白激活的交换蛋白1（Epac1）分子表达在CIH模型下特异性表达升高，下调Epac1基因表达后糖酵解水平下降，信号转导与转录激活因子4（STAT4）与Epac1启动子结合并调控Epac1表达，基此提出CIH可通过STAT4/Epac1介导线粒体代谢功能障碍，进而促进糖酵解，导致肺血管重构的发生。本项目拟利用Epac1基因敲除小鼠，构建CIH模型，结合基因干扰和免疫共沉淀等技术，研究CIH条件下STAT4/Epac1信号调控线粒体代谢及其在在肺血管重构中的作用和机制，为临床特异性防治SAS相关PH提供治疗靶点和理论基础。

Chronic intermittent hypoxia (CIH) is the most important pathophysiology of sleep apnea syndrome (SAS). The mechanism of CIH associated with pulmonary hypertension (PH), which is different from sustained hypoxia associated PH, is unknown yet. Studies have shown that CIH could lead to pulmonary vascular remodeling, and blocking CIH-related pulmonary vascular remodeling is expected to specially block the occurrence and development of SAS related PH. Our further preliminary experiments found that CIH increased the expression of cyclic adenosine monophosphate (cAMP)-activated exchange protein 1 (Epac1) and promoted glycolysis metabolism, however, the glycolysis level decreased after the knockdown of Epac1, signal transducer and activator of transcription 4 (STAT4) combined with the promoter region of Epac1 and regulated the expression of Epac1. These results suggest that CIH leads to pulmonary vascular remodeling through STAT4/Epac1 mediated mitochondrial metabolic dysfunction. We intends to use Epac1 gene knockout mice, build CIH model in vivo and in vitro, apply metabolic regulators, co-immunoprecipitation and gene interference technologies in this project, in order to study the role of STAT4/Epac1 signal in pulmonary vascular remodeling under the condition of CIH, and to explore the related mechanism about mitochondrial metabolism. This project is aimed to provide a possible therapeutic target and theoretical basis for the accurate prevention and treatment of SAS related PH.