新易感基因FAM172A干预溃疡性结肠炎的分子机制：circRNA-易感基因-内质网应激-乳球菌-UC信号轴研究

易感基因是溃疡性结肠炎（UC）形成的先决条件，但其具体信号轴尚未明确。申请人前期研究中发现一种具体机制未明的新UC易感基因FAM172A，与炎症相关结直肠癌发生密切相关。该基因受hsa_circ_0005218组蛋白甲基化或ceRNA机制的调控，可合成一种新的网腔钙结合蛋白直接调控内质网应激(ERS)影响下游炎症及免疫通路，并可抑制肠内格氏乳球菌的丰度。此外，通过预实验发现格氏乳球菌可能通过释放超氧化物诱导UC发生。因此我们推测FAM172A通过“circ_0005218-FAM172A–ERS-格氏乳球菌群-UC”信号轴，参与了UC的发病。本研究拟在前期基础上通过转基因动物实验及部分体外实验进一步探明circ_0005218、FAM172A与格氏乳球菌在UC发病过程中的相互作用及机制，验证并完善此易感基因信号轴，以阐明UC的发病机制，为其临床诊治寻找切实有效的防治新靶点。

Susceptibility gene is a prerequisite for the development of ulcerative colitis (UC), while its specific signal axis is not yet clear. In previous study conducted by this applicant, a new UC susceptibility gene FAM172A, which was associated with development of inflammatory UC, was discovered however the specific mechanism of action between FAM172Aand UC is unknow. The gene regulated by Histone methylation of hsa_circ_0005218 or mechanisms of competing endogenous RNAs, FAM172A would produce a new kind of calreticulin which can directly regulate endoplasmic reticulum stress(ERS). The ERS would affect the downstream of inflammation and immune pathway, as well as decrease the abundance of Lactococcus garvieae in small intestines. Furthermore, it is found in our pilot experiment that Lactococcus garvieae can induce the development of UC through releasing superoxide. Thus, we posit that FAM172A influent the pathogenesis of UC through circ_0005218-FAM172A–ERS-Lactococcus garvieae axis. Based on the previous findings, this research is aim to verify interactions and mechanism of action between circ_0005218, FAM172A and Lactococcus garvieae in the process of UC via transgenic animal and in vitro experiments, so as to clarifing the pathogenesis and establishing control strategies of UC.