lncRNA 4833418N02Rik活化NLRP3炎症小体在BTK缺陷型结肠炎中的作用机制研究

结肠炎是一类危害严重的炎症性疾病。BTK（Bruton tyrosine kinase）缺陷导致的结肠炎与NLRP3炎症小体的过度活化有关，但机制不明。本项目前期工作发现lncRNA 4833418N02Rik（lnc48）在BTK缺陷结肠炎患者结肠组织中高表达。我们推测：BTK缺陷可能改变下游通路引起lnc48高表达，进而促进NLRP3活化而导致了疾病。基于此，本项目拟进行下列研究：1）探讨BTK通过C/EBPα等因子影响lnc48的表达，以阐明BTK调控lnc48的机制；2）探讨lnc48介导NEK9和PKA的功能在NLRP3活化中的作用，以阐明lnc48调控NLRP3活化的机制；3）借助结肠炎模型，探讨lnc48调控NLRP3活化在结肠炎发生中的作用并评估其潜在临床应用价值。本研究有望从lncRNA角度阐明BTK缺陷导致NLRP3炎症小体活化和结肠炎的机制，为该病的治疗找到新思路。

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic autoinflammatory conditions in gastrointestinal tract. Its etiology attributes to the dysregulated intestinal immune balance caused by genetic, environmental or microbial factors. Recent years, researchers had revealed the association between BTK and development of IBD. More than thirty-fire percent of patients with X-linked agammaglobulinemia (XLA) caused by BTK deficiency display gastrointestinal abnormalities. Ten percent of all XLA patients have diagnosis of IBD. Our recent studies showed that IBD caused by BTK deficiency was associated with augmented activation of NLRP3 inflammasome. However, the mechanism by which BTK down stream signaling affects NLRP3 activation is not clear. To clarify this issue, in our preliminary studies we did a number of screening experiments and found that lncRNA 4833418N02Rik (lnc48) expression was increased in colon tissue of BTK deficient mice. Further studies showed that 4833418N02Rik regulated activation of NLRP3 inflammasome. We speculated that BTK deficiency may cause overexpression of lnc48 via its downstream signaling, lnc48 may then promotes the activation of NLRP3 inflammasome. Based on this, in the present study, we will conduct the following studies: 1) Investigate the mechanism by which lnc48 was regulated by BTK downstream signaling,such as C/EBPα; 2) Investigate the role of lnc48 in the regulation of NLRP3 inflammasome and elucidate the mechanism behind this by investigating the role of NEK9 and PKA; 3) Investigate the role of lnc48 in development of BTK deficiency caused IBD and evaluate its potential therapheutic application. These studies may elucidate the role and mechanism for lnc48 in the regulation of NLRP3 inflammasome and development of IBD caused by BTK deficiency, and may provide new strategies for the therapy of BTK deficiency caused IBD.