GMBP1短肽通过GRP78逆转胃癌耐药的分子机制

项目名称： GMBP1短肽通过GRP78逆转胃癌耐药的分子机制

项目编号： No.81472778

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： 梁树辉

作者单位： 中国人民解放军第四军医大学

项目金额： 72万元

中文摘要： 多药耐药(MDR)是导致胃癌化疗失败的重要原因，其关键分子机制仍不明确。前期工作中，我们筛选获得胃癌耐药逆转短肽GMBP1，该短肽能明显提高耐药细胞对化疗药物的敏感性，并鉴定GMBP1结合受体为葡萄糖调节蛋白GRP78。GRP78表达增高与肿瘤耐药有密切关系，我们发现GMBP1与GRP78结合后发生内化，可能通过抑制GRP78、MDR1，降低Bcl-2/Bax比值实现其耐药逆转作用，但具体机制尚不清楚。本项目拟通过蛋白质技术、分子生物学技术、生物信息学等方法，鉴定GMBP1与GRP78的结合位点，并预测其三级结构；通过流式、siRNA技术及激光共聚焦等方法，研究GMBP1细胞内化的亚细胞定位及其机制；采用蛋白质组学技术及分子生物学方法，分析介导GMBP1逆转耐药的关键分子，明确GRP78与MDR1的调控关系。本研究旨在阐明GMBP1逆转胃癌耐药的分子机制，有望为胃癌耐药逆转治疗提供新方法。

中文关键词： C07_胃肿瘤；多药耐药；GMBP1短肽；78KD葡萄糖调节蛋白

英文摘要： MDR is a major clinical obstacle in the treatment of gastric cancer(GC).using a phage display approach, we screened a peptide GMBP1 that could bind to the surface of gastric cancer MDR cells specifically,which had the potential to reverse gastric MDR phenotype and internalized into gastric cancer cells.And then GRP78 was identified as a receptor for this peptide.In the prsent study, we further investigate the targeted bind site and subcellular localization of peptide GMBP1 and GRP78.Cell-free assay that combined with FACS and Immunofluorescence stainingwill be used to investigate the underlying internalizational mechanism of GMBP1.The iTRAQ and proteomics methods will be used to explore the relationship between GMBP1, along with its receptor,and GC MDR.The prsent study researched the potential function and mechanism of GMBP1 in the reversal of GC MDR,which will provide an insight into the specific bilogical behavior of GMBP1 and GRP78 in gastric MDR and would be helpful in the treatment and reversion of GC MDR.

英文关键词： gastric cancer;mutidrug resistance;peptide GMBP1;GRP78