脑-肠轴调控巨噬细胞介导非可控炎症促进结肠癌起始细胞形成的网络关键节点研究

我们最新研究发现非可控炎症中存在一群非M1非M2巨噬细胞,它同时高表达M1和M2的特异性基因，我们将该群巨噬细胞称为M3。并发现Gαi蛋白家族和HIF1α信号通路对巨噬细胞表型转化具有重要的调控作用，巨噬细胞特异性Gαi2敲除小鼠在6-8周龄出现炎性肠息肉的表型，慢性应激可以促进该良性增生在第11周龄发展为结肠癌，具体机制未明。慢性应激可通过脑-肠轴对肠道免疫发挥重要调控作用。本项目进一步研究：1）M3巨噬细胞在慢性非可控炎症中的作用及M3巨噬细胞的来源。2）慢性应激状态下脑-肠轴的ACh和5-HT及其不同亚型受体对巨噬细胞Gαi蛋白和HIF1α表达的调控作用，阐明M3巨噬细胞诱导非可控炎症的网络关键节点，解析脑-肠轴反馈调控环路。3）慢性非可控性炎症促进结肠起始细胞形成的分子机制，重点研究LTs-IKKα-E2F1-APOBEC3B、HIF-NF-κB-Wnt、PKMζ-Hipoo-YAP-β-catenin、IL6-STAT3等信号在诱导正常结肠上皮细胞去分化中的作用及其分子机制，为探索炎癌转化的调控网络关键节点、发现肿瘤防治新靶点奠定理论基础和实验依据。

Previously we have discovered a new subtype of macrophage which expresses specific markers of M1 and M2. This population of macrophage doesn't fit into the M1/M2 classification and we call it 'M3'. Besides, we have found the pivotal role of Gαi family and HIF1α signaling in mediating macrophage polarization, macrophage-specific deletion of Gαi2 mice suffered from intestinal inflammatory polyp at 6-8 week age, which could be exacerbated into colorectal cancer by chronic stress. However, the definite mechanisms are not well understood. Chronic stress could regulate gastrointestinal immunity by brain-gut axis. In this renewing project, we will 1) Study of the function and orgin of M3 macrophage. 2) illustrate the regulation mechanisms of ACh, 5-HT and their receptors in the expression of Gαi and HIF1α in macrophages, clarify the critical node in M3 induced nonresolving inflammation, and analysis brain-gut axis reflect. 3) illustrate the molecular mechanisms of colorectal caner initiating by nonresolving inflammation, we will focus on LTs-IKKα-E2F1-APOBEC3B、HIF-NF-κB-Wnt、IL6-STAT3、PKMζ-Hipoo-YAP-β-catenin and other signaling in triggering normal colorectal epithelium cell dedifferentiation, in order to explore the critical node in inflammation-cancer transformation and discover new targets for cancer treatments.