circ-FOXO3负调控整合素β6信号促进牙周炎炎症反应的作用及机制研究

Periodontitis is a main cause of losing tooth in adult, and is related to other systemic diseases. Studies have shown that integrin β6 down regulation results in reduced level of activated TGF-β1, which is involved in the initiation and progression of periodontitis. Our preliminary data have shown that the reduced gene transcription level is involved in integrin β6 down regulation in the gingival epithelium of periodotitis. We also found that upregulation of circRNA circ-FOXO3 in periodotitis could activate transcription factor FOXO3, which was involved in ITGB6 down regulation in periodotitis. As a sponge effector, circ-FOXO3 has also been proved to be involved in regulating FOXO3 expression by other studies. We therefore hypothesize that the circ-FOXO3 functions as a miRNA sponge to regulate transcription factor FOXO3 expression, by which the transcriptional regulation of ITGB6 in periodontitis is down-regulated, hence, promoting the inflammation of periodotitis. To this end, human primary gingival epithelium cells, human periodontal tissue from surgery and periodontitis animal model will be used to explore the molecular mechanism of circ-FOXO3 promoting inflammation responses in periodontits by down-regulating integrin β6 signal. Identifying these processes may provide new insights and targets for tissue-specific upregulation of integrin β6. It may also provide new therapeutic approaches for periodontitis.

牙周炎是成年人牙齿丧失的首要原因，且与系统性疾病的发生密切相关。研究发现整合素β6表达下调导致活化的TGF-β1减少，参与牙周炎的发生和进展，但其表达下降的调控机制不清。我们前期发现转录下调参与牙周炎牙龈上皮细胞中整合素β6表达下降；circ-FOXO3在牙周炎细胞中表达增加并调节亲本基因FOXO3表达，而FOXO3参与牙周炎细胞整合素β6转录下调。 已知circ-FOXO3作为miRNA海绵分子调控FOXO3表达。我们推测circ-FOXO3可能发挥miRNA海绵分子功能增强FOXO3活性，负调控ITGB6的转录信号，促进牙周炎症反应。本项目拟用原代培养的人牙龈上皮细胞、人牙周组织标本及牙周炎动物模型，探讨circ-FOXO3调控牙周炎时整合素β6表达下调的分子机制及对牙周炎症反应的影响。本项目顺利实施将为组织特异性上调整合素β6表达提供新思路及干预靶点，进而为牙周炎治疗提供新策略。

牙周炎是成年人牙齿丧失的首要原因，且与系统性疾病的发生密切相关。研究发现整合素β6表达下调导致活化的TGF-β1减少，参与牙周炎的发生和进展，但其表达下降的调控机制不清。我们的研究发现环状RNA circ-Foxo3在牙周炎组织中高表达，且下调牙龈上皮细胞ITGB6表达，同时促进Foxo3表达，下调转录调控ITGB6表达相关转录因子JunB的表达；转录因子Foxo3参与牙周炎致病菌P.g裂解液下调上皮细胞中ITGB6表达；转录因子Foxo1与STAT3相互作用，参与牙周炎致病菌支原体菌膜蛋白FSL-1下调上皮细胞ITGB6表达。本项目的研究结果不仅从环状RNA负调控ITGB6基因转录信号的新角度解释牙周炎时ITGB6低表达，而且为转录因子之间的相互作用参与ITGB6基因表达下调提供新的直接证据。