丝氨酸/甘氨酸/一碳代谢网络（SGOC metabolic network）调控炎症性巨噬细胞活化及脓毒症病理发生的机制研究

免疫细胞根据不同的免疫功能或者免疫反应的不同阶段构建和偏好不同的代谢物质生化基础(biochemical underpinnings)，帮助其更好地进行免疫应答及维持免疫稳态平衡。一旦这种生化基础发生偏移或失衡，将导致免疫应答的失控以及炎症性疾病如脓毒症的发生。炎症性巨噬细胞的活化可被糖、脂等代谢途径及相关代谢产物所调控，但氨基酸与核苷酸代谢在其中的调控功能尚不得而知。丝氨酸、甘氨酸、一碳代谢网络(SGOC)参与细胞氨基酸、核苷酸、甲基化供体SAM合成等一系列重要代谢事件。前期研究发现炎症性巨噬细胞中SGOC代谢发生明显偏移，且其代谢流的阻断会明显降低炎症因子如IL-1β的转录表达。作用机制可能通过SGOC所支持的SAM生成进而影响特定组蛋白甲基化修饰对炎症因子的表观调控来实现。本课题将深入解析SGOC对炎症性巨噬细胞活化及脓毒症病理发生的调控功能，为临床治疗炎症性疾病提供新的理论依据。

Immune cells regulate their metabolism to support the biochemical demands for diverse immune functions and responses at different stages. Once these biochemical underpinnings are dysregulated, uncontrolled inflammatory responses and inflammatory diseases such as sepsis will occur. Glucose and lipid metabolism are appreciated to play critical roles in inflammatory macrophages, however, the regulatory functions of amino acids and nucleotides metabolism for inflammatory macrophages remains obscure. Serine, glycine, and one-carbon (SGOC) metabolic network is essential for amino acids and nucleotides metabolism, and is also required for the synthesis of methyl donor, SAM (S-adenosylmethionine). Our previous data show that SGOC metabolic network is enhanced upon LPS stimulation in pro-inflammatory macrophages. More importantly, blockade of different SGOC pathways impairs the inflammatory cytokines production including IL-1β. Mechanistically, SGOC possibly support inflammatory phenotypes of inflammatory macrophages by supporting SAM generation which is critical for the epigenetic reprogramming of certain histone methylation marks during LPS-mediated inflammation. This proposal will focus on the further study of the roles of SGOC in proinflammatory macrophages and inflammatory diseases such as sepsis. Collectively, we expect to identify a novel regulatory mechanism of inflammatory macrophages by metabolic pathways which might be targeted for the treatment of inflammatory diseases.