RANK信号通路中RANK与RYBP相互作用的结构与功能研究

项目名称： RANK信号通路中RANK与RYBP相互作用的结构与功能研究

项目编号： No.31470751

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 王新泉

作者单位： 清华大学

项目金额： 90万元

中文摘要： 人体的骨骼随着机械应力和激素水平等的变化处于骨吸收和骨重建的动态平衡过程，一旦该平衡被破坏，就会造成骨质疏松、骨硬化、关节炎、糖皮质激素诱导的骨丢失和多发性骨髓瘤等多种疾病。RANKL/RANK/OPG系统对于骨吸收和骨重建起着中心调控作用，是预防和治疗包括骨质疏松在内的骨溶解疾病的理想靶点。我们将研究RANKL/RANK/OPG系统在细胞内的信号传导机制，研究目标为RANK受体胞内结构域通过其IVVY基序与下游接头蛋白RYBP的相互作用。我们将利用结构生物学、生物化学和细胞生物学方法，解析RANK与RYBP复合物的结构，并研究鉴定RANK 信号通路中与RYBP相互作用的下游信号分子，从而揭示RANK与RYBP作用的结构基础与分子机制，进一步阐释该信号通路传导的细节。研究成果将为破骨细胞的生理和病理研究提供更坚实的基础，也将为特异性靶向破骨细胞生成的药物设计提供直接的结构信息。

中文关键词： 破骨细胞；RANK信号通路；蛋白质相互作用；结构生物学

英文摘要： The human bone system is in a dynamic and balanced progress that involves bone matrix formation mediated by osteoblasts and bone resorption mediated by osteoclasts. The disturbance of bone remodeling balance results in a broad range of bone-related diseases including osteoporosis, osteopetrosis, and anthritis. Receptor activator of NF-kB ligand (RANKL), its signaling receptor RANK, and decoy receptor osteoprotegerin (OPG), are key regulators of bone remodeling, and this molecular triad is also an attractive target to develop rational therapy for the bone-related diseases. We are going to study the molecular mechanisms underlying the RANK signaling pathway. The target is the interaction of RANK receptor through its IVVY motif with the downstream adatpor molecule RYBP. With structural biology, biochemistry, and cell biology research methods, we will determine the comlex structure of RANK with RYBP,identify and characterize downstreaming molecules that interact with RYBP in the RANK signaling pathway.The research goal is to elucidate the structural basis and molecular mechanisms of RANK-RYBP interaction. The results will help understand RANK signaling in molecular detail and also provide valuable structural information for drug development targeting the RANK signaling pathway.

英文关键词： osteoclast;RANK signaling;protein interaction;structural biology