肠道上皮是动物生理和防御的结构基础。上皮细胞脱落启动肠道更新，作为肠道最根本的细胞过程与干细胞分裂分化一同构筑起动态性的肠道上皮。非生理性的细胞脱落破坏上皮屏障功能，是肠道炎症发生发展最根本的原因。以往工作多侧重研究肠道干细胞维持和上皮细胞生物学方面的机制，尚缺少对肠上皮细胞脱落分子细胞机制的系统探索。我们的最新研究成果揭示，细菌感染激活肠道上皮Imd/NFκB天然免疫通路是导致上皮细胞脱落的重要原因。在此基础上，本项目拟继续发挥果蝇遗传模式的优势，通过比较基因组学、大规模遗传筛选等手段，系统发现并功能鉴定参与肠上皮细胞脱落的新基因，检测维持上皮细胞特性的蛋白在细胞脱落中的作用，并深入解析免疫信号调控上皮细胞脱落的分子机制。相关结果将加深对肠道上皮更新机制及宿主与微生物互作机理的认识，并为干预非生理性上皮细胞脱落提供理论依据和有效靶点，为改善动物肠道健康指明新方向。

The intestinal epithelium is not only the primary organ of digestion, but also constitutes a crucial barrier between the host and the external environment. It undergoes constant epithelial renewal through cell shedding and stem cell activation. Despite the dynamic nature of the intestinal epithelium, intestinal barrier integrity has to be tightly maintained in order to prevent penetration of harmful intraluminal entities including foreign antigens, microorganisms and their toxins. Conversely, pathological epithelial shedding compromises gut barrier function and acts as a fundamental cause of inflammatory bowel diseases. Despite extensive focus on gut regenerative growth and general epithelial biology over the past years, the molecular and cellular mechanisms underlying epithelial shedding have never been systematically investigated using a genetic approach, and consequently our knowledge on epithelial shedding remains rudimentary. We have recently revealed that the epithelium-intrinsic Imd/NFκB immune pathway triggered by enteric bacterial infection is required for intestinal epithelial shedding in Drosophila, pointing to an evolutionarily conserved crosstalk between immunity and epithelial turnover (Zhai et al., 2018 Immunity). Built on this work and taking advantage of the versatile Drosophila genetic tools, the present project is designed to obtain an in-depth understanding of immunity-induced epithelial shedding at the mechanistic level, by using a combination of the state-of-the-art approaches ranging from comparative genomics, large-scale genetic screening to in vivo live imaging. Its execution is expected to identify novel genes and pathways that contribute to epithelial shedding, elucidate the role of genes responsible for the epithelial cell polarity program in cell shedding, and further uncover regulatory mechanisms linking the immune pathway to epithelial shedding. This project is significant and timely, as it will promote a mechanistic understanding of both intestinal epithelial renewal and host-microbe interactions, two current topics with extensive focus. Because epithelial cell biology and architecture are broadly conserved, understanding the basic mechanisms that are essential for epithelial shedding will ultimately open new therapeutic avenues to combat intestinal inflammation and improve intestinal health of animals, including human.