炎症环境中GSK3β调控内质网线粒体偶联影响牙周膜干细胞再生能力的机制研究

Regeneration of periodontal ligament stem cells (PDLSCs), which is the most important cells for periodontal regeneration, is inhibited in inflammatory microenvironment. Our previous study found that GSK3β，which is the key component of Wnt pathway, regulated the regeneration of PDLSCs in inflammatory microenvironment. However, the mechanism of GSK3β regulating PDLSCs regeneration is still unknown. We also found that enhanced phosphorylation of GSK3β increased endoplasmic reticulum–mitochondria coupling and increased endoplasmic reticulum–mitochondria coupling inhibited the regeneration of PDLSCs. Thus, we hypothesize that GSK3β regulates the regeneration capacity of PDLSCs through endoplasmic reticulum–mitochondria coupling. This project will study the change of endoplasmic reticulum–mitochondria coupling in PDLSCs regulated by GSK3β, ascertain the effect and mechanism of GSK3β regulating PDLSCs differentiation through endoplasmic reticulum–mitochondria coupling, and explore the method to regenerated periodontal tissue by targeting endoplasmic reticulum–mitochondria coupling. This study will not only extend our knowledge about inflammation and endoplasmic reticulum–mitochondria coupling, but also provide the new approach to regenerated periodontal tissue by targeting endoplasmic reticulum–mitochondria coupling.

炎性微环境抑制牙周再生的重要细胞牙周膜干细胞（PDLSCs）的再生能力，本课题组以往研究发现炎性微环境中Wnt通路关键分子GSK3β调控PDLSCs的再生能力，但其分子机制仍待阐明。前期研究还发现炎性微环境中PDLSCs的内质网与线粒体偶联增加抑制PDLSCs的再生能力，而促进GSK3β磷酸化使PDLSCs的内质网线粒体偶联增加，因此推测GSK3β通过调控内质网线粒体偶联进而影响PDLSCs的再生能力。本课题将从炎症因子及GSK3β对PDLSCs内质网线粒体偶联的影响，GSK3β通过内质网线粒体偶联调控PDLSCs再生能力的作用及其分子机制，以及调控PDLSCs的内质网线粒体偶联对牙周炎动物模型治疗等不同层面展开研究。本研究丰富了炎症与内质网线粒体偶联的研究内容, 同时为牙周炎等慢性炎症性疾病治疗提供新的靶点，具有重要的理论与临床意义。

炎性微环境抑制牙周再生的重要细胞牙周膜干细胞（PDLSCs）的再生能力，但是炎症微环境抑制牙周膜干细胞再生能力的机制尚未阐明。通过本项目研究明确了炎症环境中牙周膜干细胞内质网线粒体偶联增加，线粒体钙流增加是牙周膜干细胞再生能力下降的重要原因。随后进一步发现Wnt/β-catenin信号通路抑制线粒体自噬，是导致牙周膜干细胞不良线粒体累积的重要原因；最后项目构建了靶向线粒体的纳米粒子，一方面阻断线粒体钙，另一方面增加线粒体自噬，促进不良线粒体清除，能够在牙周炎动物模型体内缓解牙周炎的牙槽骨损伤；课题尝试利用调控内质网线粒体偶联，线粒体自噬等关键机制恢复牙周膜干细胞再生能力的方法治疗牙周炎导致牙周缺损，从转化医学角度为牙周炎治疗提供新的靶点。