DAP5增强IRES-依赖的MCL1翻译和Th17存活促进肠道炎症的机制研究

多数炎症性肠病(IBD)患儿因反复肠道炎症需终生治疗，预后极差。前期研究发现黏膜Th17扩增和转分化是造成肠道炎症的重要诱因（Cell 2019），但在肠道炎症下维持Th17细胞存活的机制不清。文献报道促凋亡蛋白CASP3活化可通过DAP5识别mRNA 5’UTR的IRES元件，启动抗凋亡蛋白翻译促进细胞存活。预实验发现IBD患儿黏膜CD4+T细胞内DAP5、CASP3、抗凋亡蛋白MCL1同时增加；进一步证实Dap5缺失鼠肠炎黏膜Th17含量显著降低, Mcl-1表达降低。据此假设：Th17存活依赖于CASP3启动的DAP5-IRES-MCL1的抗凋亡通路，参与介导IBD发病。将运用Th17细胞条件性DAP5敲除鼠、体外T细胞分化, RIP-RNAseq和移植T细胞肠炎模型等阐述DAP5维持Th17存活机制。该研究将揭示维持Th17细胞存活的新机制，阐述IBD的病理基础并为治疗提供新靶标。

Children with inflammatory bowel diseases (IBD) need lifetime treatment because of recursive gut inflammation. Previous study found massive Th17 expansion and trans-differentiation in the gut mucosa is an important inducement for intestinal inflammation (Cell 2019), while the underlying mechanism for Th17 survival under inflammatory apoptotic environment is unknown. It is reported that activation of pro-apoptotic CASP3 can promote DAP5 to recognize the IRES elements within 5’UTR of mRNAs and selectively initiate anti-apoptotic proteins translation, leading to cell survival. Primary results showed that expressions of CASP3, DAP5 and anti-apoptotic protein MCL1 were co-enhanced in T cells infiltrated in the intestinal mucosa from IBD children. Further experiments showed that Th17 in the inflammatory gut mucosa of Dap5-/- mice had significantly reduced abundance and weaker anti-apoptotic Mcl-1 expression. So we hypothesize that Th17 survival depends on CASP3-initiated DAP5-IRES-MCL1 anti-apoptotic pathway, and plays important roles in IBD pathogenesis. We shall utilize Th17-conditional Dap5 knockout mice, in vitro T cell differentiation, adoptive T cell transfer colitis model, RIP-RNAseq technology to further investigate the molecular mechanism through which DAP5 maintains Th17 survival under apoptotic condition. This study shall strengthen our understanding about Th17 survival mechanisms during IBD progression, providing novel therapeutic target for IBD treatment.