IL-23/IL-17轴相关基因功能性SNP调控IL-17表达介导肠结核免疫应答的分子机制

IL-17是肠黏膜免疫的关键效应分子，但在肠结核感染中的作用尚不明确。我们发现，肠结核组织中IL-23/IL-17轴相关基因IL17/TGFβ/IL6/IL1β的表达较正常组织显著增高；在IL17基因敲除小鼠肠组织中，结核菌感染导致的病理损伤更加严重；并且各轴相关基因多态性与结核病的易感密切相关。据此，我们提出科学假说：易感SNP是否通过调控IL-17的表达水平介导肠结核的发生发展？本项目将1.通过大样本病例-对照研究探讨多个基因SNP互作与肠结核易感的相关性，建立基因型与表型的关系并筛选功能性SNP2.根据SNP所处基因座，探讨功能性SNP调控基因本身表达的分子机制3.采用SNP定点突变的巨噬细胞系或小鼠模型明确其对基因互作的影响及下游信号通路的调控。项目完成将明确SNP通过调控IL-23/IL-17轴的基因互作影响IL-17表达的分子机制，为肠结核基因型特异性个体化治疗提供理论依据。

IL-17 is critical in the intestinal mucosal immune response, but the role of IL-17 in intestinal tuberculosis is unclear. Our previous study showed that the expression of IL17 gene and TGFβ/IL6/IL1β gene in IL-23/IL-17 axis which induce the differentiation of Th17 cells were increased in intestinal tuberculosis tissues. IL17 knock out mice had severity pathology in Colorectal tissues after MTB infection. The genetic polymorphism of these genes are associated with susceptibility to pulmonary tuberculosis and extra-pulmonary tuberculosis. On this basis, we hypothesized that the polymorphism of genes affects the incidence of intestinal tuberculosis by influence IL-17 expression. But the molecular mechanism is unclear. We will use case-control study to investigate the correlation between gene SNPs and susceptibility to intestinal tuberculosis with large sample, and screen functional SNP. Then, according the location of the SNP，We will use different experiment to identify the gene function. At last, gene directed mutation macrophages in vitro or mice in vivo were used to identify the gene-gene interaction in IL-23/IL-17 axis. and the critical signal pathway. This project will elucidate the molecular pathogenesis of tuberculosis and provide a theoretical basis for targeted genotype specific therapy of tuberculosis.