自噬作为新近发现的细胞保护机制，在维持细胞内环境稳态，清除和降解异常折叠蛋白质方面发挥重要作用。研究发现，细胞在应激的条件下会通过雷帕霉素靶蛋白依赖性途径和非依赖性途径激活自噬。本课题组在上一个基金的研究中发现，氟牙症的发生可能是过量氟导致成釉细胞产生内质网应激，釉原蛋白降解障碍所致。接续的研究又发现，在一定的氟浓度范围内，大鼠成釉细胞自噬信号通路标志分子LC3、Beclin1等的表达随着氟浓度的增加而增高，而负调节因子mTOR表达降低，提示氟牙症形成过程中自噬反应的存在。在此基础上，本研究拟采用细胞培养和整体动物实验，深入探索自噬在氟致成釉细胞应激损伤后的作用及途径；应用高通量技术检测氟作用下成釉细胞microRNAs表达的变化，并以microRNA-214为线索，验证microRNA是否参与到成釉细胞自噬过程及其调控作用，期望本课题能在氟牙症的发病机制研究领域产生新突破。

Autophagy is the newly discovered cellular protection mechanism, which plays a significant role in maintaining cellular homeostasis, clearing and degrading unfolded proteins. The researches have reported that autophagy can be activated by target of rapamycin dependent pathway and independent pathway in cell stress. In the previous study, we found that dental fluorosis may be owing to endoplasmic reticulum stress of ameloblasts induced by excessive fluoride,leading to amelogenin aberrant degradation. Furthermore, the follow-up studies have found that the expressions of LC3 and Beclin1, rat ameloblast autophagy signal pathway marker molecules, was up-regulated by the increasing of fluoride in the certain fluorine concentration while the negative regulator mTOR was down-regulated, illustrating autophagy exists in dental fluorosis. Based on previous results, this study explores: (1) the pathways to autophagy in ameloblasts induced by fluoride in vitro and in vivo; (2) microRNA expression in ameloblasts with fluoride by high-throughput technique. Then we will explore whether microRNAs participate in the ameloblasts autophagy and regulation processes by taking miRNA-214 as a clue. We expect that the results can produce a new breakthrough in the pathogenesis of fluorosis.