牙周膜干细胞内GNAS调控正畸牙移动效应及机制研究

错合畸形发病率逐年升高，严重影响患者身心健康。正畸治疗疗程长，为临床治疗和患者生活带来不便。目前尚无有效的加速正畸牙移动的方法。深入理解在生物力作用下牙槽骨重建的分子机制是加速正畸牙移动研究的突破方向。其中，cAMP是介导机械信号转导和骨重建的关键调节因子。申请人发表在PNAS的研究发现GNAS-cAMP信号轴能够诱导间充质干细胞的成骨分化及刺激破骨细胞募集和活化从而加速骨重建。据此提出牙周膜干细胞内GNAS介导的骨重建能够显著影响正畸牙移动速率的猜想。本课题拟通过以牙周膜干细胞特异性驱动子转基因小鼠为基础，1）构建牙周膜特异性GNAS敲入及敲除的正畸牙移动转基因小鼠模型，2）探究牙周膜内GNAS-cAMP信号轴介导的骨重建对正畸牙移动的效应，3）阐明牙周膜干细胞内GNAS对骨重建和正畸牙移动的调控机制。为深入理解正畸牙移动分子调节机制，探索快速、安全、可靠的正畸牙移动提供前沿理论研究

The incidence of malocclusion has been increasing yearly. It has serious negative impacts the oral as well as mental health of patients. The lengthy course of orthodontic treatment poses inconvenience to both clinical management and patient's daily life. Currently, there are no widely accepted methods of accelerating orthodontic tooth movement. An in-depth understanding of the molecular mechanisms of periodontal tissue remodeling under the action of biological force is a promising research direction to advance the studies of orthodontic tooth movement. Among them, cAMP is the key regulatory of mechanical signal transduction and bone remodeling. The research published in PNAS by the applicant found that the GNAS-cAMP signaling axis is capable of inducing osteogenic differentiation of mesenchymal stem cells and stimulating the recruitment and activation of osteoclasts to accelerate bone remodeling. Based on the study, it is proposed that modulation of GNAS in the periodontal ligament stem cells (PDLSCs) can significantly affect bone remodeling and the rate of orthodontic tooth movement. This study aims 1) to construct PDLSCs-specific GNAS knock-in and knock-out transgenic mouse models, 2) to explore the effect of GNAS-cAMP signal axis on orthodontic tooth movement and 3) to explore the molecular mechanisms of bone remodeling and orthodontic tooth movement by GNAS-cAMP signal axis. Moreover, the result of this study is expected to lay a solid foundation for in-depth understanding of GNAS-mediated molecular regulation mechanisms of orthodontic tooth movement and provide a frontier theoretical basis for a fast, safe and stable method of accelerating orthodontic tooth movement.