NF-kappaB-miR-30a-SOCS-3反馈环路在尼古丁促吸烟相关性牙周炎牙周组织炎性损伤中的作用及机制研究

Periodontitis, which is the main reason for tooth loss, is one of the most common chronic oral diseases in adults. Numerous data demonstrated that smoking is one of the major risk factors for periodontitis. However, the mechanisms behind the effects of smoking on periodontal destruction are still not well understood. Our previous studies demonstrated the functional expression of α7 nAChR in periodontal ligament cells (PDLC). Nicotine could induce periodontium destruction through activation of signal pathways, such as ERK1/2, STAT3 and NF-κB, mediated by α7 nAChR. In our previous research, nicotine coud upregulate expression of mir-30a in PDLC. It is predicated that the promoter of mir-30a has several NF-κB binding points through bioinformatics. In addition, SOCS-3, the target gene of mir-30a, can regulate expression of NF-κB through supressing expression of STAT3. All these results indicating that nicotine could affect the inflammatory process of periodontium through NF-κB-mir-30a-SOCS-3 feedback loop . This study is designed to investigate the inflammatory process of PDLC and periodontium under the circumstance with the affection of normal/nicotine/α7 nAChR siRNA/mir-30a mimics and inhibitor/mir-30a agomir and antagomir, thus to explore the detailed mechanism of NF-κB-mir-30a-SOCS-3 in the inflammatory process of periodontium in smoking- associated periodontitis. We aim to provide a better theoretical basis for preventing and treating the smoking- associated periodontitis.

牙周炎严重危害口腔健康，吸烟与牙周炎密切相关但机制不明。我们前期首次证实牙周膜细胞存在烟碱型乙酰胆碱受体α7亚型（α7 nAChR）功能性表达，且尼古丁可通过该受体激活ERK/STAT3/NF-κB等信号通路，加重牙周组织破坏。预实验证实，尼古丁可上调mir-30a表达，生物信息学预测其启动子区存在多个NF-κB结合位点，而mir-30a靶基因SOCS-3可能通过STAT3影响NF-κB活化。由此推测，尼古丁激活α7 nAChR后，可通过NF-κB-mir-30a-SOCS-3环路参与牙周炎发病进程。本项目拟以牙周炎大鼠、局部干扰α7 nAChR表达和局部干扰/过表达mir-30a的大鼠及其对应的牙周膜细胞为研究模型，从分子、细胞和组织等多种水平系统探讨NF-κB-mir-30a-SOCS-3环路在吸烟相关性牙周炎牙周组织炎性损伤中的作用及机制。为吸烟相关性牙周炎的防治提供新的理论依据。

牙周炎作为口腔健康的头号杀手，主要由菌斑引起的直接细胞毒作用及宿主对菌斑微生物的免疫应答导致牙周组织损伤，进一步引起牙周支持组织丧失，导致牙齿缺失。越来越多的研究证实在牙周炎发生发展过程中存在多种miRNAs的表达变化，提示它们在牙周炎发生发展中发挥着重要的作用。吸烟作为牙周炎重要的危险因素，其主要成分尼古丁在牙周炎发生发展过程中发挥着重要作用。课题组前期研究通过构建牙周炎大鼠模型、体外培养人牙周膜细胞，尼古丁作用于实验性牙周炎大鼠和人牙周膜细胞后，发现烟碱型乙酰胆碱受体α7亚型在实验性牙周炎大鼠牙周组织和和人牙周膜细胞后均显著升高，α7 nAChR特异性拮抗剂α-银环蛇毒素可部分拮抗该效应，进而参与吸烟相关性牙周炎发生发展过程。另有研究表明，尼古丁、α7 nAChR可能通过调控多种miRNAs表达水平，参与多种心血管系统、神经系统疾病的发生发展过程。由此，我们猜想：尼古丁激活人牙周膜细胞α7 nAChR后可能会通过miRNAs进一步参与吸烟促牙周组织炎性损伤和抑制组织修复过程。本课题首先通过基因芯片发现尼古丁可特异性上调拟牙周膜细胞miR-30a的表达，进一步从基因和蛋白等多种水平系统探讨尼古丁可能通过调控牙周膜细胞miR-30a表达水平，进而调节NF-κB-miR-30a-STAT3反馈环路和CCNE2表达水平参与牙周组织炎性损伤和组织修复过程的机制；探索基于miR-30a调节途径出发降低尼古丁促牙周炎患者的牙周组织损伤和抑制牙周组织修复效应，为有效预防及治疗吸烟相关性牙周炎提供新的理论依据。

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