核酸受体ZNFX1抑制NLRP3炎症小体调控炎症性肠病的研究

NLRP3炎症小体异常活化与炎症性肠病（IBD）的进展和肠组织损伤密切相关，控制其活化水平能改善IBD进程及预后。我们发现ZNFX1是线粒体定位的病毒核酸受体并具有重要抗病毒功能，但该分子在IBD进程中的作用未知。前期研究显示，Znfx1敲除加剧小鼠IBD进展和肠组织损伤；Znfx1敲除的肠培养上清中IL-1β和IL-18水平更高；敲除的BMDMs中NLRP3呈现更高的活化程度。据此我们提出假说：ZNFX1抑制肠组织细胞NLRP3炎症小体活化，进而在IBD进展中发挥保护作用。本项目拟通过基因敲除细胞明确ZNFX1抑制NLRP3炎症小体活化的作用；利用Apex质谱系统结合经典生化分子实验探究其抑制功能的分子机制；结合小鼠IBD模型阐释ZNFX1在肠炎进展中的功能与机制。本项目有望拓展NLRP3活化调控的理论基础，并完善对ZNFX1免疫功能的认识，为IBD的临床诊断和治疗提供新的分子靶点。

Excessive activation of NLRP3 inflammasome is highly associated with the pathogenesis of inflammatory bowel disease (IBD) and intestinal tissue damage, whereas proper activation of NLRP3 inflammasome can improve the prognosis of IBD. Our previous study published in Nature Cell Biology showed that ZNFX1 is a mitochondrial-localised dsRNA sensor, which has an important antiviral function. However, the role of ZNFX1 in the pathogenesis of IBD is unknown. Our preliminary study found that IBD progression and intestinal tissue damage were exacerbated in Znfx1-/- mice. And intestinal organ culture supernatants of Znfx1-/- mice contained higher levels of IL-1β and IL-18. Moreover, NLRP3 inflammasome is much more activated in Znfx1-/- BMDMs when compared with wild-type ones. Therefore, we propose that ZNFX1 inhibits the activation of NLRP3 inflammasome in intestinal cells, and thus plays a protective role in the pathogenesis of IBD. The molecular mechanism and physiological role of ZNFX1 will be explored both in BMDMs and ZNFX1 knockout (KO) mouse models with different agonist stimulation. Furthermore, Apex2 mass spectrometry and biochemical experiments will be used to investigate the role of ZNFX1 in NLRP3 inflammasome activation. The study will not only shed new light on the regulation of NLRP3 activation but also provide a new target for IBD clinical diagnosis and therapy.