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MiR-146a通过调控Notch1 信号通路维持关节软骨内稳态的机制研究

批准号81672223 学科分类骨、关节、软组织退行性病变 ( H0609 )
项目负责人关英杰 负责人职称教授 依托单位西安交通大学
资助金额57.00
万元
项目类别面上项目 研究期限2017 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词微小核糖核酸146a;Notch1信号通路;软骨内稳态;骨性关节炎;小鼠
英文主题词microRNA-146a;Notch1 signalling pathway;Hemeostasis of cartilage;Osteoarhtritis;Mice

摘要

中文摘要 骨性关节炎(osteoarthritis, OA)是一种以关节软骨退变为主要病变的慢性疾病,其发病机制尚不清楚,尚无有效的治疗方法。多项体外研究提示miR-146a影响关节软骨细胞内稳态,但正反结论同时存在,体内实验证据尚无报道。前期实验发现,人OA软骨中miR-146a表达水平明显减少,miR-146a敲除鼠的关节过早出现OA样改变。故推测miR-146a抑制关节软骨及关节滑膜的Notch1及其下游的炎性因子IL-6,从而保护减缓OA的发生与发展进程。本课题结合miR-146a表达缺失和表达获得的小鼠模型,采用原发性OA和手术诱导OA的动物模型,从整体到细胞层次阐明本课题组的假说,为阐明miR-146a影响OA发生和发展的机理提供体内实验证据。本项目的完成将为miR-146a对维持关节软骨内稳态提供直接的基因学证据,也有助于我们研发产品用于OA的诊断和治疗。
英文摘要 Osteoarthritis (OA) afflicts millions of individuals across the world and is the most common cause of chronic disability in older adults. However, the molecular pathogenic mechanisms of OA are still unclear. Recently, microRNA(miRNA ) are believed to be powerful regulators of a range of biological processes including OA. Studies have also suggested possible involvement of miR-146a in physiological and pathological processes of OA in vitro. However, the role of miR-146a in joint cartilage homeostasis in vivo remains largely unclear. Our preliminary data shows that deficiency of miR-146a contributes to early onset of cartilage degradation and synovitis which are characteristic of OA in mice. We hypothesize that miR-146a protects the onset and progression of osteoarthritis through suppressing the expression of Notch1 and IL-6 in vivo. Our proposal will define the role of miR-146a in joint cartilage homeostasis in vivo by studying the loss and gain of function of miR-146a in genetic mouse models. We believe that the completion of this proposal will not only provide us with direct genetic evidence of miR-146a’s role in the pathogenesis of OA, but also point to agents that can be used to possibly diagnose and/or therapeutically inhibit the progression of OA.
结题摘要

成果

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