异黄酮通过ERs抑制NFκB活性从而促进骨形成的分子机制

项目名称： 异黄酮通过ERs抑制NFκB活性从而促进骨形成的分子机制

项目编号： No.81200415

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 邹世恩

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 绝经后骨质疏松症（PMOP）患病率越来越高，雌激素补充治疗可有效防治PMOP，但有副作用，异黄酮可作为替代选择。我们的研究发现：异黄酮主要通过雌激素受体（ERs）发挥骨保护作用，却没有雌激素样副作用，但ERs下游信号传导机制还不清楚。结合其他学者的研究，我们假设：异黄酮可通过ERs抑制NFκB信号通路的活性，从而促进成骨细胞骨形成。因此，本项目选取雌激素样骨保护作用最强的两种异黄酮：大豆苷原（DAI）和雌马酚（EQ），首先明确两者对去势大鼠骨及成骨细胞ERs和NFκB各信号因子表达的影响。之后用TNFα作为NFκB信号通路的激活剂，通过抑制剂和RNA干扰技术，再以DAI和EQ等处理培养的细胞，检测细胞功能和各信号因子表达水平，以及细胞核内ERs和p50/p65相互作用的情况，探索异黄酮通过ERs抑制NFκB信号通路促进骨形成的具体作用机制，为开发新型的防治PMOP药物提供新靶点和新策略。

中文关键词： 大豆苷原；雌激素；成骨细胞；雌激素受体；核因子KB

英文摘要： Postmenopausal osteoporosis (PMOP) becomes more common. Estrogen replacement therapy is an effective method for PMOP, but the side effects cannot be avoided, therefore isoflavones are substituted medication. In our previous study, isoflavones were found in playing a role in bone protection by interacting with estrogen receptors (ERs) without side effects. However the downstream signal transducting mechanism of ERs is still unknown. By combining with results of other researchers, we assume that isoflavones can promote bone formation mediated through ERs inhibiting the NFκB pathway. So, this project selected two of the strongest estrogen-like bone-protective isoflavones: daidzein (DAI) and equol (EQ). First, to clarify the effects of both isoflavones on the expression levels of ERs and NFκB signal factors in ovariectomized rats and osteoblasts. Then, to use TNFα as the activator of the NFκB signaling pathway and use inhibitors and RNA interference respectively, after that to treat cultured cells with DAI and EQ and detect the functions of cells and the expression levels of the signal factor, as well as ERs and p50/p65 interaction presented in nucleus. Finally, to reveal the molecular mechanisms of isoflavones promoting bone formation, and to provide new targets and new strategies for the development of new drugs

英文关键词： Daidzein；Estrogen；Osteoblast；Estrogen receptor；NFκB