Treg/Th17平衡对2型糖尿病颅颌骨缺损再生与修复的影响及机制研究

It is a major challenge for repair of calvarial and jaw defects with type 2 diabetes (T2D) in dental field, because the immune and molecular mechanisms involving in it are still not fully understood, which has become an urgent and critical issue to be resolved. The balance of Treg/Th17 has been reported to regulate bone regeneration, while our previous study has revealed that bone marrow mesenchymal stem cells (BMMSCs) could control the Treg/Th17. We also find that impaired immunomodulatory properties of BMMSCs resulted in disfunction of immune system. However, it is still not clear about the effects and mechanisms of Treg/Th17 dysfunction on repair of calvarial and jaw defects with T2D. Thus, in the present study, we will use T2D mice to study the effects and mechanisms of balance or imbalance between Treg/Th17 on functions of BMMSCs, such as differentiation, immunomodulatory properties, etc, and restoration of calvarial and jaw defects with T2D. Next, we will investigate whether metformin, characterized as one conventional drug to treat diabetes, could improve the immunomodulatory properties of BMMSCs, thus promoting bone regeneration of calvarial and jaw defects with T2D via Treg/Th17. Taken together, our study will discover the immune and molecular mechanisms, involving in impaired bone regeneration of calvarial and jaw defects with T2D, demonstrate new functions and potential applications of metformin, and provide theoretical and experimental evidence for improving restoration of calvarial and jaw defects with T2D in clinic in the future.

2型糖尿病患者颅颌骨缺损的再生修复是口腔医学的难题，主要原因是其再生障碍的免疫及分子机制不清，是亟待解决的关键科学问题。以往报道Treg/Th17平衡能够调控骨再生，本课题组前期研究发现骨髓干细胞具有调节Treg/Th17的能力，糖尿病小鼠骨髓干细胞免疫调控功能的异常导致机体免疫功能受损。但Treg/Th17功能异常对2型糖尿病颅颌骨再生障碍的影响及机制尚不清楚。本课题拟利用糖尿病小鼠模型在体内外研究Treg/Th17平衡与失衡对骨髓干细胞分化、免疫等功能及对2型糖尿病颅颌骨再生的影响及分子调控机制；探讨糖尿病常规用药-二甲双胍是否可通过上述机制改善骨髓干细胞免疫调节功能，进而促进2型糖尿病颅骨缺损再生。通过本研究将进一步阐明2型糖尿病颅颌骨缺损再生障碍的免疫及分子机制，拓展二甲双胍这类糖尿病常规用药的用途，为促进2型糖尿病患者颅颌骨再生修复的临床治疗提供理论依据及实验数据。

2型糖尿病伴牙周炎的牙周组织缺损的严重程度较普通慢性牙周炎患者重，且临床治疗效果差于普通慢性牙周炎，目前机制研究尚不清楚，因此，研究并揭示2型糖尿病伴牙周炎牙可能的发病机制是该领域函待解决的关键科学问题。本课题组通过收集慢性牙周炎和2型糖尿病伴牙周炎患者的牙周膜间充质干细胞(PDLSCs)，以健康PDLSCs做对照，比较其干性的变化；比较以上三组人群牙周免疫微环境的改变，检测了唾液炎性因子的表达；筛选了2型糖尿病伴牙周炎中重要miRNA,并利用体外细胞实验检测在炎性因子刺激下这些miRNA的改变，同时使用miRNA抑制剂与mimics探索这些miRNA参与2型糖尿病伴牙周炎发病的可能分子机制。我们发现牙周微环境中的TNF-α和IL-1β导致2型糖尿病牙周炎患者PDLSCs功能受损，其是通过促进2型糖尿病牙周炎患者PDLSCs的miR-9表达，从而降低E-cadherin的表达，抑制PDLSCs的Wnt通路来发挥作用。本研究揭示了2型糖尿病伴牙周炎的可能发病机制，为2型糖尿病伴牙周炎的防治提供了理论依据及实验数据。