NLRC3介导HIF1α-PDH通路调控糖代谢重编程在肺动脉高压中的机制研究

肺血管重构是肺动脉高压（PAH）重要的病理特征。研究表明肺血管重构与糖代谢紊乱密切相关，而有氧糖酵解的关键分子HIF1α在糖代谢重编程介导的肺动脉平滑肌细胞（PASMCs）活化及肺血管重构中起重要作用。NLRC3是炎症等信号通路的负调节因子，我们前期研究发现：NLRC3在PAH患者血浆及大鼠肺动脉中膜中表达均显著下降，过表达NLRC3可能介导PDH调控糖代谢重编程，抑制PASMCs活化及肺血管重构；更重要的是，我们发现HIF1α在过表达NLRC3的大鼠肺动脉中也显著下调。据此提出假说：NLRC3介导HIF1α-PDH通路调控糖代谢重编程，从而抑制PASMCs活化及肺血管重构减缓PAH的发生发展。本项目拟通过体内外实验，利用NLRC3基因编辑、组学、生物信息学及细胞分子生物学等技术，探讨NLRC3调控糖代谢重编程减缓PAH的分子机制，从而为PAH的诊治提供新的思路和靶点。

Pulmonary vascular remodeling is the main pathological feature of pulmonary arterial hypertension (PAH). Previous studies have demonstrated that glucose metabolism disorders involved in the pathogenesis of pulmonary vascular remodeling. HIF1α, as a key molecule of aerobic glycolysis, plays an important role in the pulmonary artery smooth muscle cells (PASMCs) activation and pulmonary vascular remodeling mediated by glucose metabolism reprogramming. NLRC3 has been described as a negative regulator of inflammatory signaling pathways. Our previous studies have already showed that the expression of NLRC3 was significantly decreased in plasma of patients and pulmonary arterial medial membrane of MCT induced PAH animal model. We also found that, by targeting PDH, NLCR3 could inhibit PASMCs activation and pulmonary vascular remodeling by regulating glucose metabolism reprogramming in PAH. More importantly, we also found that HIF1α was significantly down regulated in the pulmonary artery of NLRC3 overexpressed rats. Based on those interesting findings, we hypothesize that, by mediating HIF1α-PDH pathway, NLRC3 regulates glucose metabolism reprogramming to inhibit PASMCs activation and pulmonary vascular remodeling, thus finally alleviating the pathogenesis of PAH. Therefore, using NLRC3 transgenic and gene knockout animals, omics, bioinformatics and cell molecular biology techniques, we set to explore the specific molecular mechanism of NLRC3 regulated glucose metabolism reprogramming in PAH by both in vivo and in vitro experiments. This project aims to provide a deep understanding and new targets for precision diagnosis and treatment of PAH.