SATB2-Nanog-mTOR轴调控BMSCs衰老及其在颌骨增龄性骨量丢失中的作用

项目名称： SATB2-Nanog-mTOR轴调控BMSCs衰老及其在颌骨增龄性骨量丢失中的作用

项目编号： No.81470723

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： 江宏兵

作者单位： 南京医科大学

项目金额： 73万元

中文摘要： 因骨髓间充质干细胞（BMSCs）衰老引起的增龄性骨量丢失直接影响颌骨再生修复，其中干性衰减和雷帕霉素靶蛋白(mTOR)激活是BMSCs衰老的关键因素。然而，决定干性特征的Nanog和mTOR通路在BMSCs衰老中的调控机制仍不清楚。我们前期研究发现：核基质蛋白SATB2在颌骨BMSCs干性维持与衰老中具有重要作用。本项目拟在分析颌骨BMSCs衰老过程中SATB2-Nanog-mTOR通路分子时空表达规律的基础上，构建体外细胞衰老和大鼠衰老模型，采用SATB2过表达/基因沉默等手段，阐明SATB2-Nanog-mTOR调控轴在BMSCs衰老过程中的作用机制，并探索SATB2修饰BMSCs移植以逆转BMSCs衰老、促进成骨、抑制破骨、改善颌骨骨结构的可行性和有效性。本研究不仅有助于深入认识BMSCs衰老机制及其在颌骨增龄性骨量丢失中的作用，而且有可能为防治颌骨增龄性骨量丢失提供新的策略和靶点。

中文关键词： 骨髓间充质干细胞；衰老；多潜能性；SATB2；增龄性骨量丢失

英文摘要： Aging-related bone loss resulting from bone marrow mesenchymal stem cells (BMSCs) senescence has significant deleterious effects on bone regeneration and repair in jaws. Progressive attenuation of stemness and activation of mTOR are key pathogenic drivers underlying this process. However, the detailed functions of pluripotency factor Nanog and mTOR pathway during BMSCs senescence remains largely unknown. Our previous studies have revealed that SATB2 plays vital roles in stmness and senescence regulation of mandibular BMSCs. In the present study, firstly, the temporospatial expression patterns of SATB2-Nanog-mTOR signaling axis will be analyzed in aging mandibular BMSCs. Secondly, the models of cellular senescence in vitro and the aging rats are employed to explore the roles and associated regulatory mechanisms of SATB2-Nanog-mTOR axis by SATB2 overexpression/ knockdown in combined with rapamycin inhibitor. Lastly, the therapeutic effects of SATB2-modified BMSCs in vivo transplantation are further determined to reverse BMSCs senescence as well as to promote osteogenesis and inhibit osteoclastogenesis, thus improving the bone microstructure. Collectively, our findings may provide insights into the biological roles of BMSCs senescence behind aging-related bone loss, and offer novel therapeutic target to prevent aging-related bone loss in jaws.

英文关键词： Bone marrow mesenchymal stem cell;Aging;Pluripotency;Special AT-rich sequence-binding protein 2;Aging-related bone loss