肥胖相关巨噬细胞在牙周组织破坏中的作用及其表观遗传学机制

Obesity, characterized with low-grade systematic inflammatory state, is the risk factor for various metabolic and inflammatory diseases. It has been shown that obesity is also the risk factor to promote the development and progress of periodontitis by various clinical studies, but the underlying mechanism is unknown. The phenotype dysregulation of macrophages in adipose tissue is the main pathological mechanism for systematic inflammatory state in obesity. Our previous studies have shown that macrophage phenotype transition occurred in visceral adipose tissue in obese rats under periodontal infection. The phenotype dysregulation of macrophages is controlled largely through epigenetic mechanisms, our peliminary study indicated that HDAC1,2 was involved in the shaping mechanism of macrophage phenotypes in periodontium under obesity. Therefore, focused on macrophage phenotype dysregulation,this project aims to explore the critical epigenetic mechanism and signal molecules behind macrophage phenotype dysregulation, deepening into HDAC1,2,3/NF-kappa B p65 acetylation/histone acetylation/macrophage phenotype related target genes AXIS, and to elucidate the cellular and molecular mechanisms between obesity and periodontitis. It is expected that this study would provide evidences for solving at both cellular and molecular levels how obesity and infection resulting in low-grade systematic inflammatory state, and help to find a new immune intervention strategy systemically and locally for periodontally-compromised obese patients and provide potential epigenetic target for drugs to treat obesity, periodontitis, as well as various chronic inflammatory diseases.

肥胖机体特征性的低度系统性慢性炎症使其成为人体一系列慢性疾病的危险因子。肥胖促进牙周炎的发生发展也为众多临床研究所证明，但生物学机制尚不清楚。脂肪组织巨噬细胞表型异常是导致肥胖状态下系统慢性炎症的主要病理机制。课题组前期研究表明，在牙周感染状态下肥胖大鼠内脏脂肪组织巨噬细胞表型发生改变。巨噬细胞表型异常很大程度上受控于表观遗传学机制，课题组预实验提示，HDAC1,2可能参与肥胖性巨噬细胞表型在牙周组织的调节机制。本项目以巨噬细胞表型异常为纽带，以HDAC/NF-κB p65乙酰化/组蛋白乙酰化/巨噬细胞表型相关基因为纵深线，探索巨噬细胞表型背后的关键表观遗传学机制和信号分子，阐述肥胖与牙周炎相关联的细胞和分子机制，并为从细胞和分子水平揭示肥胖、感染如何导致机体慢性炎症状态提供实验依据，为肥胖与牙周炎在系统和局部的免疫干预及慢性炎症性疾病的防治提供新途径和潜在的表观遗传学药物靶点。

肥胖机体特征性的低度系统性慢性炎症使其成为人体一系列慢性疾病的危险因子。肥胖促进牙周炎的发生发展也为众多临床研究所证明，但生物学机制尚不清楚。脂肪组织巨噬细胞表型异常是导致肥胖状态下系统慢性炎症的主要病理机制。课题组前期研究表明，在牙周感染状态下肥胖大鼠内脏脂肪组织巨噬细胞表型发生改变。巨噬细胞表型异常很大程度上受控于表观遗传学机制，课题组预实验提示，HDAC1,2可能参与肥胖性巨噬细胞表型在牙周组织的调节机制。本项目以巨噬细胞表型异常为纽带，以HDAC/NF-κB p65乙酰化/组蛋白乙酰化/巨噬细胞表型相关基因为纵深线，探索巨噬细胞表型背后的关键表观遗传学机制和信号分子，阐述肥胖与牙周炎相关联的细胞和分子机制，并为从细胞和分子水平揭示肥胖、感染如何导致机体慢性炎症状态提供实验依据，为肥胖与牙周炎在系统和局部的免疫干预及慢性炎症性疾病的防治提供新途径和潜在的表观遗传学药物靶点。