基于成分-靶点相关网络的二至丸调控骨重建的作用机制

项目名称： 基于成分-靶点相关网络的二至丸调控骨重建的作用机制

项目编号： No.81473545

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： 刘艳秋

作者单位： 大连医科大学

项目金额： 72万元

中文摘要： 骨重建是由分子网络调控的骨形成与骨吸收介导的功能耦联过程。骨重建失衡是骨质疏松的关键致病因素。经典方剂-二至丸临床用于治疗骨质疏松，可调控骨重建多环节，但目前对其研究以单靶点评价为主，且调控骨重建的多靶成分认识不够充分和深入。本课题拟构建调控骨形成与骨吸收耦联的骨重建生物信号网络，结合前期建立的细胞共培养体系，反映骨形成的Wnt/beta-catenin、骨吸收的RANKL/RANK、ER等途径的动态变化规律，以此为二至丸及其成分调控骨重建的作用评价提供多靶标的整合环境。在不同靶标可同时分析基础上，结合分子模拟等手段，计算二至丸成分与靶点的结合能力，为从靶点及其调控网络角度研究揭示二至丸的多靶点、整合作用机理。本研究建立的生物网络建模-成分靶点对接-调控网络构建的二至丸调控骨重建的方法体系为中药多成分、多靶点、整合调节机制研究提供了新的研究模式，有望加快二至丸防治骨质疏松的创新中药研发。

中文关键词： 骨重建；二至丸；生物网络；多靶点；整合调节

英文摘要： A biological network that mediates the coupling of bone formation and bone resorption, maintains the homestasis of bone remodeling.The imbalance of the biological network resulted in bone-related diseases,such as osteoporosis. Er-Zhi-Wan is a kidney-tonifying traditional Chinese formulation.Modern research shows that antiosteoporotic activity of Er-Zhi-Wan is carried out by regulation of bone resorption and bone formation, to develop an new class of dual-action therapeutic agent for clinic usage. However,current knowledge whether Er-Zhi-Wan and its components have multi-target effect should be evaluated.This project is to establish the bilogical network involved in regulating the couple of bone degradation and bone building,based on the anlysis of the signaling pathways of Wnt/beta-catenin,ER,and RANKL/RANK in the co-culture of bone mesenchymal stem cells, pre-osteoclasts and ovarian follicular granulosa cells. Further, the impact of Er-Zhi-Wan and its components on the biological network is investigated. In addition, by docking the crystal structure of targets for compounds,we detemine the binding affinity of targets for active constituents.We expect to demonstrate that the compounds target the sinaling system,therefore simultaneously reducing bone destruction and increasing bone synthesis.These studies are expected to show for the first time a role for Er-Zhi-Wan in regulation of biological network of bone remodeling. The outcomes of the project have signifcant implication for understanding the mechansim by which Er-Zhi-Wan regulates bone remodeling,and for developing the novel dual-action agents from the traditioanl Chinese formulation of Er-Zhi-Wan. Additionally, these established methods will contribute to validating the multi-target mechanism of other traditional Chinese medicine.

英文关键词： Bone remodeling;Er-Zhi-Wan;Biological network;Multi-target;Integrated regulation