PGC1-α介导的线粒体动力学失衡在伴糖尿病牙周炎发生中的作用及机制研究

Oxidative stress was recognized as a crucial pathogenesis in the development and progression of diabetic periodontitis (DP). However, the underlying mechanisms are not fully understood. Our previous studies revealed that mitochondrial dysfunction was a crucial pathogenesis in the periodontal destruction of DP. Furthermore, our preliminary results indicated that the mitochondrial dysfunction involved in DP was closely related with decreased expression of PPARγcoactivator1-α (PGC1-α) and enhanced mitochondrial fission. PGC1-α represents a critical regulator of mitochondrial function and fusion/fission dynamic balance, thus we rasied the hypothesis that PGC1-α mediated impairment of fusion/fission balance was a key pathogenesis in the progression of DP. To verify this hypothesis, we will explore the specific mechanisms underlying oxidative stress induced DP from the aspects of mitochondrial dynamics and PGC1-α. We will establish in vitro cell model of DP and use chemical and genetic approaches to unveil the regulatory role of PGC1-α in cell injury and impairment of mitochondrial dynamics. We will further explore the regulating effects of PGC1-α and related mechanism by adopting DP in vivo animal model with PGC1-α activator and inhibitor of mitochondrial fission used. This comprehensive study will not only provide new insights into the pathological mechanism of DP, but also make a solid foundation for the development of new therapeutic strategies and targets in the prevention or treatment of DP.

氧化应激是伴糖尿病牙周炎（DP）发生的重要病理基础，但具体机制不明。课题组前期研究表明，氧化应激介导的DP组织破坏以线粒体功能障碍为关键特征。同时预实验揭示，DP相关的线粒体功能障碍与PGC1-α低表达及线粒体分裂活跃密切相关。鉴于PGC1-α是线粒体功能及融合分裂动力学平衡的中枢调控分子，故提出“PGC1-α介导的线粒体动力学失衡是DP的关键病理机制”。为此，本项目拟从线粒体动力学的新视角，以PGC1-α为切入点，探究氧化应激促使DP发生的具体机制：构建DP体外细胞模型，采用化学及基因手段正反双重探究PGC1-α在细胞损伤中的作用，并从线粒体分裂相关蛋白入手阐明PGC1-α调节线粒体动力学失衡的机制；联合DP体内动物模型，应用PGC1-α激动剂及线粒体分裂抑制剂，最终验证PGC1-α的确切作用及其对线粒体动力学的调控机制。本项目有望揭示DP发生的新病理机制，并为其防治提供新途径与新靶点。

氧化应激是伴糖尿病牙周炎（DP）发生的重要病理基础，但具体机制不明。课题组前期研究表明，氧化应激介导的DP组织破坏以线粒体功能障碍为关键特征。同时预实验揭示，DP相关的线粒体功能障碍与PGC1-α低表达及线粒体分裂活跃密切相关。鉴于PGC1-α是线粒体功能及融合分裂动力学平衡的中枢调控分子，故提出“PGC1-α介导的线粒体动力学失衡是DP的关键病理机制”。为此，本项目拟从线粒体动力学的新视角，探究糖尿病牙周炎背景下PGC1-α的确切作用及线粒体相关调控机制。结果提示：PGC1-α在DP发生发展中起重要作用，其激动剂可有效缓解氧化应激造成的细胞损伤和线粒体异常进而抑制DP发展。同时，中药水飞蓟宾可通过激活PGC1-α从而缓解DP进展。本项目有望揭示DP发生的新病理机制，并为其防治提供新途径与新靶点。