内皮细胞外囊泡介导Th17/Treg失衡在ARDS中作用及机制

目前研究关注T细胞免疫在ARDS中的效应，我们新近资料显示CD4+T细胞中Th17/Treg失衡介导ARDS早期炎症反应，严重影响患者预后，且内皮细胞外囊泡（EC-EV）可介导ARDS病理损伤，但具体调控途径尚缺乏了解。通过转录组分析、生信预测、BioGPS数据库及Hub基因筛选，结合体外实验强烈提示EC-EV表面分子CD44可结合T细胞表面L-选择素活化T细胞，并可能通过PTPN2介导Th17/Treg失衡。本项目拟分别调控CD44、L-选择素及PTPN2，并使用i-TRAQ筛查关键蛋白，探讨EC-EV调控Th17/Treg失衡的分子机制；临床研究探讨EC-EV中关键蛋白与ARDS患者疾病严重程度及预后的关系，从分子→细胞→动物→临床整体论证EC-EV介导Th17/Treg失衡是ARDS早期炎症失控的新机制，为开展针对性防治开辟新方向。

Previous study has been focusing on the effect of T cell immunity in ARDS for a long time. It has been shown in our study that Th17/Treg imbalance in CD4+ T cells mediated inflammation in the early phase of ARDS, resulting in poor prognosis of ARDS patients. We also found that endothelial cell-derived extracellular vesicles (EC-EV) could induce lung injury in vitro, but the plausible mechanism is still unclear. According to integrated results of transcriptome analysis, bioinformatics prediction, BioGPS database, Hub gene screening and experiments in vitro, it was suggested that CD44 on EC-EV could activate T cells binding to L-selectin, resulting in Th17/Treg imbalance through PTPN2. In this project we plan to (1) explore the molecular mechanism of EC-EV induced Th17/Treg imbalance by regulating CD44, L-selectin and PTPN2 separately. (2) screen biomarkers of EC-EV by using i-TRAQ. (3) evaluate the relationship between the biomarkers and the severity and prognosis of ARDS patients in clinical studies. In conclusion, we aim to verify the hypothesis that EC-EV induced Th17 / Treg imbalance is a new mechanism of inflammation in the early phase of ARDS from bench to bedside, and explore a new direction for precise treatment for ARDS patients.