基于组织内源性干细胞分子病理分析和干预的自发性骨关节炎模型的鉴定和比较研究

项目名称： 基于组织内源性干细胞分子病理分析和干预的自发性骨关节炎模型的鉴定和比较研究

项目编号： No.81472126

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周光前

作者单位： 深圳大学

项目金额： 150万元

中文摘要： 本项目提出从两方面验证和确立Hartly豚鼠和STR/ort小鼠对老年性骨关节炎（OA）的代表性和适用性：1）研究组织内源性干细胞在OA发病中的异常改变和调控机理，明确其对OA疾病的核心作用；2）验证和评价激活或补充干细胞对OA的防治作用及其作用机理。 OA是环境因素与遗传因素长期交互作用的综合结果，特征为软骨细胞质量减低及胞外基质合成-分解失衡。Hartly豚鼠和STR/ort小鼠随年长关节发生退变，病理特征和病程规律与人类OA类似，但组织细胞及分子病理学所知甚少，限制了它们的应用价值。本项目提出组织内源性干细胞为OA的关键致病因素，首先研究OA组织干细胞的异常改变，建立iPSC细胞疾病模型，解析内源性干细胞的关键调控分子或机制；继而应用这些动物和细胞模型，比较分析从干预关键分子或表观遗传机制入手激活内源性干细胞对OA的防治效果。本项目可望显著促进自发性OA鼠模型的转化医学应用。

中文关键词： 老年性骨关节炎；间充质干细胞；自发性OA动物模型；组织内源性干细胞激活；诱导多能干细胞

英文摘要： Osteoarthrits (OA) occurs in high incidence in the elder population, caused by multiple interplaying microenvironmental factors under certain genetic backgrounds.The halmark of OA are the declination of the number and function of chondrocytes and the over-degradation of extracellular matrix in the articular cartilage and the sounding tissues. With aging, both Hartly guinea pigs and STR/ort mice spontaneously develop the pathology that resembles human OA. However, the key signaling pathways, epigenetic mechanisms,and the cellular alternations that may contribute to the disease remain poorly understood in these animals, limiting their application in translational research of OA. This application proposes that the endogeneous mesenchymal stem cells residing in the articular cartilofage are the target of disease-causing factors and both the activation of endogeneous MSCs or implantation of MSCs could be effective therapy of OA. We will first investigate the functional properties of OA cartilage-derived MSCs, deciphere the key signaling pathways invovled in the regulation of MSCs. Certain agents activating MSCs will be tested for their role in activating key signaling pathways and epigenetic mechanisms. In the meanwhile, the efficiency of intraarticular injection of MSCs in haltering OA progression will be evalualted. The proposed work will significantely harness the appplication of the studied animal models in OA translational medicine.

英文关键词： Senile osteoarthritis;Mesenchymal stem cells(MSCs);Spontaneous Senile ostroarthritis(OA) animal models;Activation of endogeneous stem cells;Iduced pluriopotent stem cells(iPSC)