肠上皮细胞（IEC）在人类炎症性肠病（IBD）和其动物模型DSS诱导的结肠炎（DIC）中发挥多种关键性的作用。去泛素化酶OTUB1可以调控包括NF-κB在内的多种信号通路，在自发免疫性疾病、神经退行性疾病和癌症等疾病中发挥重要的作用。然而，OTUB1在肠炎中的作用尚不明确。我们前期的研究发现，IEC中的OTUB1在DIC中表达上调。为了研究OTUB1的体内功能，我们构建了Villin-CreERT2 OTUB1fl/fl小鼠，该小鼠IEC中的OTUB1可以受他莫昔芬诱导敲除。与对照组小鼠相比，Villin-CreERT2 OTUB1fl/fl小鼠对DIC更加敏感，提示OTUB1具有缓解结肠炎的作用。在本项目中，我们拟通过转录组测序、蛋白质组学和构建OTUB1突变体小鼠等技术，阐明IEC特异性OTUB1在DIC中的功能及其调控信号转导的分子机制，为IBD的防治提供潜在的新靶点。

Intestinal epithelial cells (IECs) play critical roles in inflammatory bowel disease (IBD) and its animal model DSS-induced colitis (DIC). OTUB1, a K48-specific deubiquitinating enzyme (DUB), has been shown to regulate multiple signaling pathways including the NF-κB pathway. Functionally, OTUB1 plays key roles in various diseases such as autoimmune diseases, Alzheimer’s disease, and cancer, but its function in DIC and IBD is still unknown. In our preliminary study, we found that protein levels of OTUB1 were upregulated in IECs during DIC. To study the in vivo function of OTUB1, we generated Villin-CreERT2 OTUB1fl/fl mice, in which OTUB1 could be ablated specifically in IECs upon treatment with tamoxifen. In comparison to OTUB1fl/fl control mice, Villin-CreERT2 OTUB1fl/fl mice were more susceptible to DSS-induced acute and chronic colitis, suggesting that IEC-specific OTUB1 is protective in this disease model. In the proposed project, we will apply a broad range of techniques, such as RNA sequencing, proteomics, and construction of OTUB1 mutant mice, to elucidate the functional role of IEC-specific OTUB1 in DIC as well as the mechanism of action of OTUB1 in signal transduction, thereby providing potential novel targets for the treatment of IBD.