非编码RNA共调控网络对溃疡性结肠炎免疫失衡调控机制研究

重度溃疡性结肠炎（UC）死亡率高，虽然TNFa阻断剂开启治疗新纪元，但仍有30-40%为难治性，从调控网络中寻找多层面治疗靶点是必然需求。VitD受体（VDR）调控保护性肠道免疫调节，但单纯补充维生素并不能很好启动保护性免疫调节。我们假设如果勾画出该通路的调控网络，可以探寻新的药物靶标。由于非编码RNA有细胞特异性、组织特异性和时相性在免疫网络调控中具有重要意义。本课题组前期从相同UC组织标本中进行miRNA、lncRNA和mRNA array分析，构建了非编码RNA (lncRNA，miR125b, miR23c)调控网络的预测图，从预测图中获得VDR相关通路中新的靶点（NFKBIA等)。本项目通过动物模型、细胞系、临床标本，探寻和验证非编码RNA在UC发病中的共调控关系，以VDR/NFKBIA/NFkB通路为主要关注点，探寻UC不同时段发病机制，确定潜在药物靶标，为应用研究奠定基础。

Although anti-tumor necrosis factor-alpha (TNFa) therapies have opened a new era for ulcerative colitis (UC) management, approximately one third of patients with severe UC are refractory to drug treatment. Severe UC is associated with a measurable mortality. It has been suggested that immunological imbalance may contribute to pathogenesis of UC. Among immune modulators vitamin D receptor (VDR) is known to guide the protective immune. Clinical studies by our group have shown that the deficiency of Vitamin D is significantly associated with severe UC. However, the clinical efficacy was poor in UC patients supplied with vitamin D, which suggests that supplement vitamin D alone may not be enough to balance and active protective immune. We hypothesize that analyzing immune regulatory network diagram with the biological information will identify therapeutic targets. Because non-coding RNA(miRNA and lncRNA) have the properties of cell specific, organization specific and timing it may play an important role in regulating immune network. In a pilot study, we have built the regulatory network from the same samples of miRNA array,lncRNAarray, and miRNA array , and acquired VDR pathway diagram and some new possible targets ( NFKBIA, etc). In this project, we will use animal models, cell lines, and clinical samples to explore the co-regulation relationship of non-coding RNA (lncRNA，miR125b, miR23c)on pathogenesis of UC. The focus will be on VDR/NFKBIA/NFkb pathway, non coding RNA regulating the intestinal immune evolution mechanism, and cell functions. Overall, understanding UC pathogenesis from non-coding RNA regulatory networks and immune protective pathways will offer possible therapeutic targets and facilitate from research to clinical translation.