TGR5调控骨质重建的分子机制研究

项目名称： TGR5调控骨质重建的分子机制研究

项目编号： No.81472048

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： 罗剑

作者单位： 华东师范大学

项目金额： 72万元

中文摘要： 胆汁酸受体TGR5参与体内多种代谢过程，包括糖代谢，脂代谢，能量代谢等，此外，TGR5的激动剂已被证明能抑制肥胖、II型糖尿病、脂肪肝、高脂血症、动脉粥样硬化等代谢相关疾病。是否TGR5参与骨代谢还未见报道。申请人的前期工作基础已经表明，TGR5在成骨细胞和破骨细胞中均有表达，胆汁酸和TGR5的激动剂能抑制破骨细胞分化且促进成骨细胞分化。体内实验也表明Tgr5基因敲除小鼠的骨质下降，TGR5的小分子激动剂能抑制卵巢切除导致的骨质丢失。这些结果均表明TGR5能调控骨质重建（骨代谢）过程。因此，本项目将结合遗传学、药理学、生物化学等手段着重研究TGR5调控骨质重建过程中的分子机理，明确TGR5在成骨细胞和破骨细胞分化及功能中的作用，并且通过骨质疏松小鼠模型和药理学分析确定TGR5在骨质疏松症发生中的作用。本项目的开展将为骨质疏松症的防治提供新的药物靶标，为后继的药物研发打下坚实的基础。

中文关键词： 骨代谢；胆汁酸受体；成骨细胞；破骨细胞；骨质疏松

英文摘要： Bile acid receptor TGR5 has been reported to regulate glucose metabolism, insulin sensitivity, lipid metabolism. Moreover, the agonist of TGR5 has been shown to inhibit type 2 diabetes, fatty liver, hyperlipidemia, and atherosclerosis. Therefore, it's reasonable to speculate that TGR5 also have a role in the regulation of bone metabolism. Our preliminary data had shown that it had the expression of Tgr5 in osteoblast and osteoclast, the bile acid and the TGR5 agonist regulated the differentiation of osteoblasts and osteoclasts. Our in vivo data also showed that the bone mass was decreased in Tgr5-defiency mouse; the agonist of TGR5 prevented the ovariectomy-induced bone loss. All of the data indicate that TGR5 regulates bone metabolism. In this study, using a combination of pharmacological and genetic gain- and loss-of function studies in vivo, we will study the molecular mechanism of TGR5 regulating bone remodeling, figure out the function of TGR5 modulating osteoporosis. Our study may contribute a promising drug target in multiple diseases that result in bone loss including osteoporosis.

英文关键词： bone metabolism;bile acid receptor;osteoblast;osteoclast;osteoporosis