新型脂联素受体激动剂AdipoAI通过APPL1/MyD88/c-Maf新途径抑制糖尿病型牙周炎破骨细胞分化的作用和机制研究

破骨细胞分化过度激活是糖尿病型牙周炎病情加重的关键因素之一，靶向抑制其分化是临床治疗药物开发的重要方向。申请人前期筛选发现新型脂联素受体激动剂AdipoAI抑制破骨细胞分化、改善糖尿病大鼠牙周炎牙槽骨缺损，但机制尚不明确。芯片结合敲除实验证实靶分子c-Maf调控破骨分化关键转录因子NFATc1；同时发现AdipoAI处理破骨前体细胞后APPL1、MyD88等差异表达。据此提出：APPL1/MyD88/c-Maf新途径参与AdipoAI抑制破骨分化，改善糖尿病型牙周炎。本项目以AdipoAI为切入点，拟研究c-Maf在AdipoAI抑制破骨细胞分化中的关键作用；通过慢病毒基因操作结合免疫荧光、Co-IP、pull-down及BIAcore探究APPL1与MyD88、c-Maf与NFATc1之间的信号转导，为AdipoAI作为治疗糖尿病型牙周炎的候选药物提供理论基础。

Over activation of osteoclast differentiation plays a key role in the progress of diabetes-associated periodontitis and eliminating the process is an important direction for the development of therapeutic drugs. In our preliminary study, AdipoAI, a new adiponectin receptor agonist, could eliminate the bone resorption in experimental periodontitis model in diabetic rats by inhibiting osteoclast differentiation. However, the regulating mechanism is not clear. We also found that c-Maf could regulate NFATc1 and had different expressions of APPL1 and MyD88 in this process. We proposed that AdipoAI inhibits osteoclast differentiation via APPL1/MyD88/c-Maf pathway. Therefore, we aim to explore the key role of c-Maf in osteoclast differentiation, and reveal the signal transduction between APPL1 and MyD88 by using lentiviral plasmid, immunofluorescence, Co-IP, pull-down and BIAcore, which can provide new strategies for the drug development of diabetes-associated periodontitis with anti-osteoclast differentiation.