新型LncRNA作为ceRNA介导miR-23b-5p调控琥珀酸代谢异常在口腔扁平苔藓炎性进展中的作用

Oral lichen planus (OLP) is a chronic inflammatory disease in oral mucosa with frequent recurrence , but etiology is still unknown. Abnormal succinate metabolism and highly expressed succinate dehydrogenase (SDH) were found to involve in the inflammatory progression of OLP in our previous research, but the up-regulation mechanism is still unknown. Preliminary experiment results showed that LncRNA AC083837.1 was highly expressed in OLP lesions, and it was predicted by miRanda software that it could compete with miR-23b-5p to participate in the regulation of SDH. Based on this, we speculate that the LncRNA AC083837.1/miR-23b-5p/SDH signal axis may participate in the inflammatory progression of OLP by regulating the succinate metabolism. This project intends to use OLP tissue specimens and keratinocyte cell line to confirm the expressions of the LncRNA signal axis, further elucidate the molecular mechanism of the LncRNA regulation of SDH expression and its effect on the biological behaviors of OLP through abnormal succinate metabolism. This result will reveal the role of succinate abnormality induced by LncRNA in the promotion of OLP inflammatory progression and provide new targets for OLP treatment and intervention.

口腔扁平苔藓(oral lichen planus,OLP)是一种口腔黏膜慢性炎性疾病，反复迁延且病因未明。申请人前期已发现琥珀酸代谢异常参与了OLP的炎性进展，琥珀酸脱氢酶（SDH）亦高表达，但上调机制未知。预实验结果发现LncRNA AC083837.1在OLP病变组织高表达，通过miRanda软件预测其可能竞争性的与miR-23b-5p结合参与对SDH的调控，据此推论LncRNA AC083837.1/miR-23b-5p/SDH信号轴可能通过调控琥珀酸的代谢参与OLP的炎性进展。本项目拟以OLP病变组织和OLP角质形成细胞系为模型，首先确认该LncRNA信号轴的表达，进一步阐明该LncRNA调控SDH表达的分子机制及其通过琥珀酸代谢异常对OLP生物学行为的影响。该结果将为代谢失衡在OLP炎性进展中的作用研究拓展新思路,并为OLP的治疗及干预提供新靶点。

口腔扁平苔藓（oral lichen planus,OLP）作为一种常见的口腔黏膜慢性炎性疾病，上皮病变角质形成细胞的增殖凋亡紊乱是其重要病理特征。本课题组前期研究结果发现OLP炎性进展过程中琥珀酸在上皮角质形成细胞中的异常表达可致其增殖凋亡紊乱，但其上调机制未明。近年研究发现，长链非编码RNA（long nocoding RNA,LncRNA）可通过多种途径调控糖代谢引起多种细胞增殖凋亡紊乱，在炎性疾病的发生发展中发挥重要作用。但在OLP角质形成细胞中的作用鲜有报道。.主要研究内容包括：1、通过转录组测序技术在组织水平筛选OLP炎性进展过程中与琥珀酸代谢异常相关的LncRNA并进行临床标本的验证。2、通过体外实验明确LncRNA AC083837.1的改变对SDHA的影响。3、通过miRanda软件对LncRNA AC083837.1和SDHA进行靶向miRNA预测，得到关键的miRNA；进一步通过体外实验明确LncRNA AC083837.1调控SDHA的ceRNA分子机制。4、初步探索LncRNA AC083837.1/miR-23b-5p/SDHA调控琥珀酸代谢对细胞增殖与凋亡的影响。.研究结果显示：1、LncRNA AC083837.1与琥珀酸代谢关键酶SDHA主要定位在OLP病变组织的上皮层中，并在OLP的炎性进展过程中的表达存在差异。2、LncRNA AC083837.1的改变可以影响SDHA的表达水平。3、LncRNA AC083837.1可通过竞争性结合miR-23b-5p调控SDHA的表达； LncRNA AC083837.1/miR-23b-5p/SDHA轴可以影响OLP的琥珀酸代谢。4、LncRNA AC083837.1/miR-23b-5p/SDHA轴通过调控琥珀酸促进角质形成细胞的凋亡，抑制其增殖。.科学意义：本研究以代谢组学与OLP的关系为基础，进一步揭示了LncRNA AC083837.1和miR-23b-5p通过SDH这一核心分子在OLP炎性进展中的重要作用，可能作为OLP炎性进展的标记物，为OLP炎症进展机制研究、临床诊疗及其它非可控性炎性疾病提供了新思路及重要的理论意义。