不同表型Th17及特征性分泌因子调控牙槽骨破坏效应差异的相关机制研究

Th17 and its typical secretion of IL-17 has a strong ability in inducing tissue inflammation and regulating RANKL expression related with bone destruction, which is closely associated with the incidence and progression of periodontitis. Recently, two phenotypes of Th17 cells secreting different characteristic factors have been identified in vivo. But their pathogenicity in periodontal diseases, the difference of ability in promoting osteoclast activity, and the regulatory mechanism of cytokine secretion are still unknown. On a previous project, our study group has established bone resorption model by inducing osteoclast precursor cell differentiation to study the regulating mechanism of bone resorption supernatant on osteoblast proliferation, as well as its influence on the resorption-reconstruction equilibrium of alveolar bone. On the basis of these experiments, the present grant focus on the research line that the accumulative difference of two phenotypes of Th17 cells will affect the expression level of RANKL which could promote osteoclast activation. Objectives of study are to make clear the osteoclast activity promoting effect of IL-17+Th17, IL-17+IFN-γ+Th17 cells and their specific secretion by taking intervening measures on animal model of alveolar bone absorption and molecular cell biology experiments. In order to reveal the molecular mechanism of the mutual transformation the two phenotypes of Th17 cells that secrect different cytokines, the signal transduction pathway of Th17 cells to activate IFN-γ and IL-17 expression will be studied. The expected result may provide a new theoretical explanation on the relationship between the incidence of periodontitis and host immune, as well as offer new perspectives to guide the development of clinical strategy for the prevention and treatment of peridontal disease.

Th17及特征分泌的IL-17有强烈致炎和调控RANKL表达骨破坏效应，与牙周炎发病及进展密切相关。新发现人体内存在分泌不同特征性因子的两种表型Th17细胞，两者牙周致病性、促破骨活动效应差异、及因子分泌的调控机制尚未明了；课题组在诱导破骨前体细胞分化建立骨吸收模型，研究其培养上清对成骨细胞的增殖分化调控机制，进而影响牙槽骨稳定的前期实验基础上，本项目着眼不同表型Th17细胞聚集差异影响RANKL表达水平、促破骨细胞活化的研究思路，通过干预牙槽骨吸收动物模型和分子细胞生物学实验，明确IL-17+Th17和IL-17+IFN-γ+Th17细胞及特征性分泌因子的促破骨效应；并通过Th17细胞活化IFN-γ、IL-17表达的相关信号传导通路研究，揭示调控两种细胞分泌不同细胞因子及相互转化的分子机制，以期为牙周炎发病与宿主免疫之间的关系提供新的理论解释，为指导临床科学制定牙周病防治方案开拓新视角。

Th17 及特征分泌的 IL-17 有强烈致炎和调控 RANKL 表达骨破坏效应， 与牙周炎发病及进展密切相关，但其具体的牙周致病性、促破骨活动效应差异的调控机制尚未明了。本研究明确了Th1、Th2和Th17细胞及其特征性分泌因子与慢性牙周炎发病密切相关。Th1及Th17细胞共同参与了慢性牙周炎局部组织的炎症反应；不同细胞因子诱导不同表型IL-17+ Th17与IL-17+IFN-γ+Th17细胞存在差异性，单IL-23能诱导两种表型Th17细胞生成，而TGF-β对IL-17+IFN-γ+Th17细胞分化起抑制作用；不同表型Th17细胞特征性分泌因子（IL-17/IFN-γ）促进大鼠实验性牙周炎模型牙周病变过程中相互拮抗；IL-17可通过JAK2/STAT3通路，促进成骨细胞分泌RANKL，抑制OPG表达从而促进破骨细胞分化，但IL-17与IFN-γ在调控破骨细胞分化过程中起拮抗作用；IL-17以AKT2依赖方式促进MC3T3-E1细胞成骨分化与钙化，IFN-γ促进作用不明显，且两者呈拮抗效应。上述研究结果为牙周炎发病与宿主免疫之间的关系提供新的理论解释，为指导临床科学制定牙周病防治方案开拓新视角，有较高学术价值及创新性。

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