脓毒症是感染或应激引起的免疫应答失控所致的危及生命的器官功能障碍，并伴随着细胞能量代谢异常，二者之间存在密切的联系。α-KG作为TCA循环的中间产物之一，是多种表观遗传调控酶类的辅助因子，并能参与调节炎症反应，被认为是能量代谢和炎症调控之间重要的桥梁。我们前期发现α-KG在脓毒症患者血清中有动态变化，给予α-KG可以抑制巨噬细胞炎症反应，并能诱导SCARA5表达上调。SCARA5是巨噬细胞表面的一类重要模式识别受体，在抗炎反应过程中发挥重要作用。我们推测α-KG通过表观遗传调控SCARA5表达并影响巨噬细胞能量代谢的重编程，调节脓毒症进程。本项目将利用利用新型探针模型SoNAR小鼠监测脓毒症巨噬细胞的能量代谢改变，利用LysMCre TET2f/f小鼠解析α-KG通过DNA甲基化调控SCARA5表达，阐明α-KG对脓毒症巨噬细胞炎症反应的调节机制，为脓毒症治疗提供新的分子靶点和研究思路。

Sepsis, characterized by life-threatening organ dysfunction, is caused by the out of control inflammatory response due to infection or stress, along with changes of cell energy metabolism and there is a close connection between them. α-KG, one of the intermediate product of TCA cycle, is the cofactor of a variety of enzymes related to epigenetic regulation. It could regulate the inflammatory response and is thought to be the important bridge between energy metabolism and inflammation. We have found that the content of α-KG changed in the serum of patients with sepsis. It could inhibit the inflammatory response of macrophages and induce the expression of SCARA5. SCARA5 is an important pattern recognition receptor of macrophages and plays an important role in the anti-inflammatory reactions. Our hypothesis is α-KG inhibit the inflammatory response and ameliorate the endotoxin tolerance in the early and late stage of sepsis, by inducing SCARA5 through epigenetic regulation and reprogramming of energy metabolism in macrophages. The project will use SoNAR，a new genetic fluorescent probe model, detecting metabolism changes in mice macrophages dynamically, and use LysMCre TET2f/f mice demonstrating α-KG regulate the expression of SCARA5 by DNA demethylation. Our study will clarify the mechanism of α-KG regulating macrophage inflammatory response in sepsis and provide new molecular targets for sepsis treatment and research strategy.