中性粒细胞胞外陷阱（NETs）诱导内皮细胞焦亡促发2型糖尿病血栓形成的机制研究

2型糖尿病（T2DM）是一组高血糖伴胰岛素抵抗为特征的代谢性疾病。血管内皮细胞损伤引起的血栓形成是T2DM的常见并发症。申请人首次发现T2DM胰岛素抵抗可刺激中性粒细胞释放胞外陷阱（NETs），促进血栓形成。本研究拟利用转录组学、基因敲除、生物膜载药等技术，研究胰岛素抵抗促发NETs释放的机制；揭示NETs经Calreticulin/GPCR/NF-κB信号轴和cathepsin G酶切作用调控焦亡刺激因子IL-1β、GSDMD-N诱导内皮细胞焦亡，及焦亡内皮细胞释放S100A8/A9活化血小板形成血栓的调控网络；明确自体红细胞载药系统靶向降解NETs在治疗T2DM血栓中的作用。本研究可揭示NETs诱导内皮细胞焦亡促发T2DM血栓形成的分子调节机制，有望为T2DM血栓形成的临床标志物研发及精准治疗提供理论基础。

Type 2 diabetes mellitus (T2DM) is a group of metabolic diseases characterized by hyperglycemia with insulin resistance. Thrombosis caused by vascular endothelial cell injury is a common complication of T2DM. Our study found, for the first time that T2DM with insulin resistance stimulates the release of extracellular traps (NETs) from neutrophils to promote thrombosis. In the present study, we intend to use transcriptomics, gene knockout technique, biomembrane drug delivery system to study the mechanism of insulin induced NETs release via IR/p38 MAPK/ROS pathway, the effect of NETs on vascular endothelial cell injury, the molecular mechanism that NETs induced endothelial cell pyroptosis through activation calreticulin/GPCR/NF-κB axis to produce pro-IL-1β and GSDMD which will be cut into their mature form (IL-1β and GSDMD-N) by engulfed-cathepsin G. Finally, we will construct an autologous erythrocyte drug delivery system, and study its effects on digestion NETs-induced thrombus in vitro and in vivo. This study will reveal the molecular regulation mechanism of NETs-induced endothelial cell pyroptosis to induce thrombosis in T2DM, which is expected to provide a theoretical basis for clinical biomarker discovery and precision treatment of thrombosis in T2DM.