巨噬细胞介导牙周炎促进肥胖性胰岛素抵抗的表观遗传调控

项目名称： 巨噬细胞介导牙周炎促进肥胖性胰岛素抵抗的表观遗传调控

项目编号： No.81371151

项目类型： 面上项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 章锦才

作者单位： 中国科学院大学

项目金额： 70万元

中文摘要： 近年大量研究证据表明，肥胖，作为糖尿病、心血管疾病等系统病的重要危险因素，与牙周炎相互关联的印证，敲响了全球公共健康的警钟。尽管流行病学证据日益累积，但二者相互关联的机理知之甚少。课题组最新研究首次表明，实验性牙周炎促进肥胖性胰岛素抵抗加剧；脂肪组织慢性炎症是联系肥胖和胰岛素抵抗的关键，巨噬细胞的浸润激活在脂肪组织炎症中处于核心地位。最近研究表明Jmjd3-IRF4是调节巨噬细胞激活的重要信号通路，TLR4是联系天然免疫与肥胖性胰岛素抵抗的重要免疫模式受体，巨噬细胞中JNK信号通路对肥胖性胰岛素抵抗的形成不可或缺。探寻三者在患牙周炎的肥胖机体内的交互作用，将从表观遗传学角度揭示代谢、免疫、炎症间的内在联系，由此探究牙周炎促发肥胖性胰岛素抵抗的关键信号途径，正是本项目的重点。基于表观遗传修饰的可逆性，项目的开展将为靶向干预脂肪组织巨噬细胞异常激活途径提供策略,从而预防牙周炎促发肥胖相关疾病。

中文关键词： 牙周炎;肥胖;胰岛素抵抗;巨噬细胞;表观遗传学

英文摘要： Periodontitis and obesity, a most important risk factor of diabetes and cardiovascular disease, have been correlated in many studies recently, which becomes a new threat to the global health. However, the mechanism by which they interplay is unknown, despite the cumulative epidemiological evidences. More recently, it was found by our team that experimental periodontitis contributes to obesity-related insulin resistance, accompanied by increased chronic inflammation in adipose tissue which has been known critical in obesity-related metabolic diseases. In the inflammatory process, macrophage infiltration and activation is believed to play a key role. Some signaling pathways have recently been shown important in the function of macrophage, including: 1) Jmjd3-IRF4 axis, a histone demethylase depended signaling which modulates macrophage activation; 2) TLR4, a key pattern recognition receptor linking innate immune to obesity-related insulin resistance; 3) and JNK signaling, which is indispensable for resulting obesity-related insulin resistance. Our project here aiming to elucidate the crosstalk between these signaling pathways and find the key ones through which periodontits contributes to obesity-related insulin resistance, would clarify the connection between metabolism, immune and inflammation from a new perspective of epigenetics. Based on the reversibility of epigenetic modification, our project would provide some critical signaling molecules to be targeted in the abnormal activation pathway of macrophage in adipose tissue, which would help prevent the onset of obesity-related diseases from promotion by periodontitis.

英文关键词： periodontitis;obesity;insulin resistance;macrophage;epigenetics