乙酰转移酶MORF调控内质网应激影响牙周膜干细胞再生能力的机制研究

The most important cells for periodontal regeneration are periodontal ligament stem cells (PDLSCs). Changed epigenetic modification leads to impaired regeneration capacity of PDLSCs. Our previous study found that expression of histone acetyltransferases MORF was decreased in PDLSCs derived from periodontitis, which caused the decreased regeneration capacity. However, the mechanism of MORF regulating PDLSCs regeneration is still unknown. Endoplasmic reticulum stress (ERS) is closely related with the regeneration of stem cells. Our further findings showed that knockdown of MORF activated the ERS in PDLSCs. Therefore, we hypothesize that MORF regulates the regeneration capacity of PDLSCs through endoplasmic reticulum stress. This project will study the differentiation of PDLSCs regulated by MORF and ERS, ascertain the effect and mechanism of MORF regulating PDLSCs differentiation through ERS, and explore the method to regenerated periodontal tissue by targeting ERS. This study will not only extend our knowledge about epigenetic modification and ERS, but also provide the new approach to regenerated periodontal tissue by targeting ERS.

作为牙周组织内最为重要的功能细胞群，牙周膜干细胞（PDLSCs）表观遗传修饰改变使其再生能力发生变化。本课题组前期研究发现炎症PDLSCs乙酰转移酶MORF表达下调导致其再生能力下降，然而MORF调控PDLSCs再生的机制尚不明确。以往研究证实内质网应激（ERS）与干细胞再生密切相关，敲除PDLSCs的MORF后其ERS被激活，我们由此推测MORF可能通过调控ERS从而影响PDLSCs的再生能力。为此，本研究拟从MORF及ERS对PDLSCs分化的影响，MORF通过ERS调控PDLSCs分化的作用和分子机制，以及调控ERS原位修复牙周缺损四个方面探讨MORF调控ERS与PDLSCs再生能力之间的关系。本研究有望丰富表观遗传修饰与内质网应激相关的研究内容, 并为通过调控PDLSCs内质网应激水平修复牙周缺损提供重要的理论和实验依据。

作为牙周组织内最为重要的功能细胞群，牙周膜干细胞（PDLSCs）表观遗传修饰改变使其再生能力发生变化。本课题组前期研究发现炎症PDLSCs乙酰转移酶MORF表达下调导致其再生能力下降，然而MORF调控PDLSCs再生的机制尚不明确。以往研究证实内质网应激（ERS）与干细胞再生密切相关，敲除PDLSCs的MORF后其ERS被激活，我们由此推测MORF可能通过调控ERS从而影响PDLSCs的再生能力。为此，本研究从MORF及ERS对PDLSCs分化的影响，MORF通过ERS调控PDLSCs分化的作用和分子机制，以及调控ERS原位修复牙周缺损四个方面探讨MORF调控ERS与PDLSCs再生能力之间的关系。课题研究发现牙周膜干细胞在炎症微环境中MORF表达下调，内质网应激被激活。激活的内质网应激导致下游UPR反应的PERK通路活化进一步导致PDLSCs成骨分化下降。而MORF被进一步证明是发挥转录抑制子的作用直接作用于PERK的启动子区域，MORF下调因此PERK通路激活。课题组建立了大鼠牙周炎模型证明移植PERK通路能够逆转大鼠牙周炎发生，为牙周炎治疗提供新的靶点。本研究有望丰富表观遗传修饰与内质网应激相关的研究内容, 并为通过调控PDLSCs内质网应激水平修复牙周缺损提供重要的理论和实验依据。..