利用转基因斑马鱼研究abcb4基因在肿瘤耐药中的机制

项目名称： 利用转基因斑马鱼研究abcb4基因在肿瘤耐药中的机制

项目编号： No.31460312

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 发育生物学与生殖生物学

项目作者： 舒莉萍

作者单位： 贵州医科大学

项目金额： 45万元

中文摘要： 多药耐药是导致肿瘤药物治疗失败的主要原因，基于多药耐药机制建立理想动物模型对于抗肿瘤药物的开发和临床前期筛选具有重要价值。ATP结合盒转运蛋白家族（ABC）中的MDR1（P-gP/ABCB1）主要介导药物的外排，从而导致肿瘤药物发生多药耐药，是肿瘤耐药中的关键因素。而目前研究常用的Mdr1a-/-基因敲除小鼠，无法实现诱导性MDR1的表达，遂只能用于肠道主动运输方面的研究，而无法成为耐药药物筛选的模型。本课题利用斑马鱼独特的生物学和遗传学优势，拟建立一个abcb4特异性启动子驱动egfp基因的转基因动物Tg(abcb4:EGFP)模型，通过药物诱导MDR1的表达，深入探讨MDR1在多药耐药中的机制，进一步阐明肿瘤产生多药耐药的可能机制，以填补高通量的、活体的、多药耐药筛选动物模型的空白，对于临床抗肿瘤新药的筛选，具有重要的科学价值和巨大的应用前景。

中文关键词： 斑马鱼；多药耐药；abcb4；P糖蛋白；MDR1

英文摘要： Multidrug resistance is the main cause of failure of tumor therapy, so based on Multidrug resistant mechanism to establish an ideal animal model has important value for anti-tumor drug development and clinical preliminary screening. ATP binding cassette transporter protein (ABC) in MDR1 is mediated by drug efflux, resulting in the development of multidrug resistance in cancer drug which is the reason why MDR1 is a key factor in the multidrug resistance in cancer. At present, research on Mdr1a-/- gene knockout mice, unable to realize the expression induced by MDR1, and can only be used for the study on the mechanism of drug resistance, and cannot become resistant drug screening model. Our research group take full advantages of zebrafish's unique biology and genetics advantages, namely the regulation network of development and human highly conserved, embryo development in vitro and transparent, can be directly dynamic monitoring in the whole developmental process, high throughput, small molecule drugs reflect the screening of small volume, easy absorption and relative economy, conbining with sing the tracer transgenic zebrafish technology, and establish the MDR1 transgenic model of EGFP markers in zebrafish, inducing the expression of MDR1 to investigate the mechanism of MDR1 on multidrug resistance. We may further elucidate the mechanisms of tumor multidrug resistance, in order to establish an ideal animal model which could be used for drug screening, and provides an important basis to pre clinical for drug screening.

英文关键词： zebrafish;multidrug resistance;ATP-binding cassette sub-family B member 4;P-glycoprotein;multidrug resistance 1