细菌脂多糖（lipopolysaccharide, LPS）能够诱导天然免疫特别是巨噬细胞所介导的炎症反应，与许多炎症性疾病（如脓毒性休克）密切相关。尽管已有许多研究，巨噬细胞中被LPS激活的信号传导机制仍未彻底搞清，无法对此过程进行有效干预来抑制炎症反应。为更深入地研究信号传导通路，我们充分利用基因编辑和定量质谱的最新技术，在近期发展出了一套系统性的研究方法，可以对一信号复合物进行其形成和解离的定量动态分析，并能挖掘出复合物上的未知蛋白。本申请拟使用此方法，系统、定量地在巨噬细胞中分析至少九个LPS信号节点上的复合物，进而构建定量动态细胞信号传导图谱，填补此信号通路中尚存的信息空隙；并发现鉴定LPS信号通路中的新的调节蛋白，在细胞系水平、原代细胞及成体水平揭示其功能。此课题的完成可以为研究其它信号通路提供方法学范本，其实验结果将会回答领域内的若干重要问题，为治疗炎症性疾病的提供新思路。

Bacterial lipopolysaccharide（LPS）via activating innate immune system, especially macrophages, to trigger inflammation, and the inflammation associates with many inflammatory diseases such as septic shock. Although LPS signaling is one of the most studied topics in innate immunity, there are still many gaps in our knowledge on the mechanisms of LPS-induced macrophage reactions, which limits our ability to inhibit LPS-mediated inflammation. Current research techniques may already be close to reach their limitation in obtaining further information of the mechanisms of LPS-induced macrophage activation. Here we will use our newly developed method to systematically and quantitatively analyze the signaling pathways activated by LPS in macrophages, and assemble a dynamic signaling map of LPS signaling that should bridge the gaps in our understanding of LPS signaling. We should also be able to identify a number of new components in LPS pathway during this process. Biochemical, genetic, molecular and cell biology approaches will be used to characterize the function of these newly identified proteins. The in vivo functions of these new proteins will be also validated. We believe that this collaborative study will bring new mechanistic insights into the mechanisms of inflammation, and thus provide new ideas for treating inflammatory diseases.