PPARγ在骨关节炎AGEs/RAGE细胞信号通路中的作用及机制研究

项目名称： PPARγ在骨关节炎AGEs/RAGE细胞信号通路中的作用及机制研究

项目编号： No.81201432

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 陈铖

作者单位： 湖南师范大学

项目金额： 23万元

中文摘要： 晚期糖基化终末产物(AGEs)是导致骨关节炎(OA)的关键物质，可通过与受体(RAGE)结合激活细胞内信号通路引起一系列细胞损伤效应，但机制尚未完全阐明；过氧化物酶体增生物激活受体γ(PPARγ)在OA患者和动物模型中表达明显下调，可能与OA病理机制相关。本研究首次提出PPARγ下调是RAGE介导的细胞信号通路中一个重要环节的假说，并运用分子生物学技术、基因沉默技术、动物实验及临床观察、多因素分析等方法从细胞、动物模型及人体三个角度加以验证，探究PPARγ与其他信号分子的关系，力图揭示AGEs致OA发病的分子生物学机制，明确PPARγ的作用和意义，观察PPARγ激动剂匹格列酮对AGEs引起软骨损伤的保护作用及对AGEs致病的细胞内外途径进行多重阻断对OA进程的影响，为发现新的OA干预靶点，阻止OA进行性发展，实现有效防治OA提供可靠的实验和理论依据，并为匹格列酮老药新用的临床开发奠定基础

中文关键词： 骨关节炎；晚期糖基化终末产物；过氧化物酶体增生物激活受体γ；吡格列酮；信号通路

英文摘要： Advanced Glycation End products（AGEs）, considered a molecular mechanism for aging as a risk factor in Osteoarthritis (OA), combined with the receptor of AGEs(RAGE) result in cell damage through activation of intracellular signaling pathways. However, it has been poorly understood for the precise mechanism. Peroxisome proliferator-activated receptor gamma (PPARγ) has been demonstrated decreased expression significantly in OA animal models and OA patients. This evidence suggests that PPARγ may play important role for the pathogenesis of the OA. we proposed a hypothesis firstly that the down-regulated of PPARγ expression may play an important role in RAGE-mediated cell signaling pathways during the disease. In this study, Numerous experiment have established in vivo and in vitro, including molecular biology techniques, gene silencing technology, multivariate analysis, and so on. By using these methods to elucidate: a relationships between PPARγ signaling and other cellular signaling; and molecular role of the AGEs during the pathogenesis of OA; and role of PPARγ and pioglitazone (a PPARγ agonist) protect mechanism in cartilage damage during the OA; and influences of OA process by blocking the AGEs signaling pathways. The present study might offer valuable new clues to effective prevention and control OA process bas

英文关键词： Osteoarthritis；Advanced Glycation End products；peroxisome proliferator-activated receptor-γ；Pioglitazone；signal pathway