抑制腹泻是治疗包括炎症性肠病在内的腹泻性疾病的关键。我们偶然发现仅在肠上皮细胞中过表达T-bet可导致严重的腹泻，并引发转基因小鼠死亡。T-bet上调促进Cl-分泌的离子通道CFTR并同时下调促进Cl-吸收的转运体DRA，导致电解质和水分丢失。YY1能特异性的在肠上皮细胞中调节CFTR/DRA的表达，并且YY1的作用受过表达的T-bet调控。海洋药物Neoechinulin B对TNBS诱导的肠炎有保护作用，其作用为下调YY1和CFTR并上调DRA。初步实验证明Neoechinulin B可通过YY1-CFTR/DRA通路实现对肠炎的保护作用，但确切机制仍不清楚。我们将采用多种肠炎及腹泻模型和培养的小肠organoid模型，运用CRISPR/Cas9敲除技术及胞内蛋白热迁移实验等方法进一步确证Neoechinulin B以及YY1-CFTR/DRA通路对肠道炎症及腹泻性疾病的保护作用。

The incidence of inflammatory bowel disease (IBD) is increasing in China. The available drugs are limited and the effect is not ideal. Long term chronic diarrhea increases the suffering and economic burden of the patient, and the inhibition of diarrhea becomes the key to the treatment of diarrheal diseases, including IBD. We found that overexpression of T-bet in intestinal epithelial cells can lead to severe diarrhea and result in the death of these transgenic mice. T-bet can upregulate the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) that promotes the secretion of Cl- in intestinal epithelial cells, and simultaneously down regulate the Cl-/HCO3- exchanger down-regulated in adenoma (DRA, also named Slc26a3) that promotes Cl- uptake, resulting in electrolyte and water loss. Selective CFTR inhibitors merely and partially antagonized the over expression of T-bet. Yin-Yang 1 (YY1) can specifically regulate the expression of CFTR/DRA in intestinal epithelial cells, and the role of YY1 is regulated by the expressed T-bet. Marine natural product Neoechinulin B has protective effect on TNBS induced mouse enteritis, and its effect is down regulation of YY1 and CFTR and up regulation of DRA. Preliminary experiments have shown that Neoechinulin B can protect the enteritis through YY1-CFTR/DRA pathway, but the exact mechanism is still unclear. We will use a variety of enteritis and diarrhea model and cultured intestinal organoid model, using CRISPR/Cas9 knockout technology and cellular thermal shift assay (CETSA) experiments further confirmed the protective efeect of Neoechinulin B and YY1-CFTR/DRA pathway on intestinal inflammation and diarrhea disease. It can also provide new therapeutic targets for the treatment of diarrheal diseases.