脓毒症是世界范围内的主要死亡原因，至今尚无特异有效的治疗药物，其中脓毒症免疫抑制带来的相关死亡和医疗负担尤其显著。巨噬细胞功能异常重编程在脓毒症内毒素耐受形成过程中发挥关键作用。我们前期研究发现ADP核糖化因子鸟苷酸交换因子1（BIG1）很可能参与巨噬细胞内毒素耐受的形成，髓系敲除BIG1可阻断内毒素耐受的形成；免疫共沉淀发现其与SET1/MLL甲基转移酶家族复合物共同的核心组件Dpy-30相互作用。在此基础上，本项目将利用已建立的髓系BIG1基因条件敲除小鼠，从整体动物和细胞分子水平进一步探讨BIG1在巨噬细胞内毒素耐受形成中的作用；同时从Dpy-30介导的表观遗传调控与能量代谢角度探讨BIG1调控巨噬细胞功能重编程的确切分子机制。本项目的实施有可能为脓毒症免疫抑制的治疗提供新靶标。

Sepsis is the leading cause of death worldwide. So far, there is no specific and effective drug available. The death and medical burden caused by immunosuppression of sepsis is significant. Macrophage dysfunction reprogramming plays a key role in the formation of endotoxin tolerance in sepsis. Our previous studies have found that ADP ribosylation factor guanosine exchange factor 1 (BIG1) may be involved in the endotoxin tolerance process of macrophages. The myeloid knockout of BIG1 blocked the formation of endotoxin tolerance in mice. Immunoprecipitation showed that BIG1 interacted with Dpy-30, a core component of SET1/MLL methyltransferase family complexes. In this project, we will further investigate the role of BIG1 during endotoxin tolerance in macrophages using established myeloid BIG1 gene conditional knockout mice, and the cell model; and explore the precise molecular mechanism of BIG1 in regulating macrophage functional reprogramming through Dpy-30-mediated epigenetic regulation and energy metabolism. The implementation of this project may provide a new therapeutic target for immunosuppression of sepsis.