免疫麻痹是脓毒症死亡的主要原因之一，但机制不明。单核巨噬细胞有氧糖酵解受损、促炎因子分泌能力下降是免疫麻痹的主要特征。我们前期发现免疫麻痹时有氧糖酵解调节蛋白mTOR活性降低，内质网功能异常，单核细胞的负性免疫分子Trex1表达升高。由于Trex1 C末端可与内质网OST复合体相互作用，这可调控内质网功能而影响mTOR活性，因此，我们提出研究假设Trex1通过其C末端调控内质网途径介导免疫麻痹状态下单核巨噬细胞炎症及有氧糖酵解；本项目拟围绕单核巨噬细胞，开展以下研究：首先，探讨Trex1在脓毒症免疫麻痹进程中的表达变化。其次，研究Trex1 C末端对脓毒症免疫麻代谢和炎症的影响；然后，探讨OST复合体在Trex1介导免疫麻痹细胞代谢与炎症中的作用；最后，探讨OST复合体亚基与Trex1 C介导免疫麻痹相互关系。本研究将有助于深入认识脓毒症免疫麻痹的发生机制，为改善免疫麻痹提供新的分子靶点。

Sepsis-induced immunoparalysis is one of the major reasons caused the death of septic patients, but the mechanism remains to be identied. The impaired aerobic glycolysis (Warburg effect) and the downregulated ability of proinflammatory cytokines production are the main features in monocyte/macrophage during immunoparalysis. Our preliminary study showed that the disfunction of the endoplasmic reticulum (ER), and the activation of mTOR which is involved in the anaerobic glycolysis were decreased in the immune cells from septic immunoparalysis. At the same time, we found the expression of Trex1 was increased which is related to the host response in monocytes from the hyporeactive septic patients. The Trex1 C terminal could modulate the function of ER involved in the activation of mTOR pathway. According these findings we hypothesize that Trex1 promote immunoparalysis via inhibiting the mTOR signaling pathway mediated the Warburg effect and inflammation in sepsis, which is related to the function of its C terminal. We will thus test this hypothesis in present proposal as follow. Aim1, we will observe the change of Trex1 in human monocytes and mice macrophages during the progression of immunoparalysis. Aim2, we are also going to investigating the effects of Trex1 C terminal on the glycolysis and inflammation of monocytes or macrophages during septic immunoparalysis. Aim3, the interaction of Trex1 and oligosaccharyltransferase (OST) complex of ER will be studied, and we will conform that the relationship between OST and mTOR pathway mediated anaerobic glycolysis as well as inflammation. Aim4, the relationship between the OST subunits and Trex1 C terminal mediated mediated anaerobic glycolysis and inflammation will be investigated. This research may helpful to further clarify the mechanism of septic immunoparalysis and provide a new molecular target to reduce immunoparalysis.