硫氧还蛋白-1通过调节内质网应激IRE1α通路对脓毒症发挥保护作用的机制研究

脓毒症是临床危重患者最主要的死亡原因，但发病机理尚未完全清楚。近年研究发现内质网应激可以通过肌醇需求酶1α(IRE1α)信号通路导致炎症反应，并且内质网应激可能激活NLRP3炎症小体。硫氧还蛋白-1(Thioredoxin 1，Trx-1)是体内重要的氧化应激调节蛋白，具有抗氧化、抗凋亡和抗炎等生物学活性。我们前期研究发现Trx-1通过抑制内质网应激相关的炎症反应在脓毒症小鼠中发挥保护作用，但具体分子机理尚不明确。因此本项目将使用Trx-1转基因小鼠和小鼠巨噬细胞制作脓毒症模型，以IRE1α信号通路为切入点，通过质粒转染及RNA干扰，调控Trx-1和IRE1α的表达，检测炎症介质和细胞凋亡，观察内质网应激IRE1α/NF-κB信号通路和IRE1α/NLRP3炎症小体相关蛋白的变化趋势，探讨Trx-1在脓毒症内质网应激中发挥保护作用的分子机制。本项目可为脓毒症的治疗提供理论依据。

Sepsis is the main cause of death in critically ill patients, pathogenesis of which is still unclear. Recent studies indicate that endoplasmic reticulum stress can cause inflammation by inositol-requiring enzyme 1α(IRE 1α) signaling pathway. What’s more, endoplasmic reticulum stress may also activate NLRP3 inflammasome. Thioredoxin-1 (Trx-1) is an important protein of regulating oxidative stress. It plays a crucial role in the anti-oxidation, anti-apoptosis and anti-inflammation. Our previous study found that Trx-1 played a protective role in sepsis mice by regulating inflammatory response through suppressing endoplasmic reticulum stress. However, the molecular mechanism remains unknown. Therefore, this project will use Trx-1 transgenic mice and mouse macrophages to make septic model in vivo and vitro. Taking IRE1αsignaling pathway as the breakthrough point, the project will investigate inflammation and cell apoptosis and determine the changes of IRE1α/ NF kappa B signal pathway and IRE1α/NLRP3 inflammasome associated proteins in endoplasmic reticulum stress by using plasmid transfection and RNA interferon to regulate the expression of Trx-1 and IRE1α. The aim of this project is to explore the the molecular mechanism of Trx-1 in endoplasmic reticulum stress in sepsis. Our project will provide theory evidence for the treatment of sepsis.