氢醌依赖NF-κB信号转导途径对骨髓间充质干细胞MDR1基因和P-糖蛋白表达的影响

项目名称： 氢醌依赖NF-κB信号转导途径对骨髓间充质干细胞MDR1基因和P-糖蛋白表达的影响

项目编号： No.81202160

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 预防医学、地方病学、职业病学、放射医学

项目作者： 黄简抒

作者单位： 复旦大学

项目金额： 23万元

中文摘要： MDR1基因编码的P-gp使细胞泵出外源性物质，保护细胞免受损害，NF-κB是调控MDR1转录的重要信号途径，骨髓间充质干细胞（BMSCs）经遗传修饰后可以不同形式治疗疾病。我们在前期研究中发现，携带MDR1 3435 TT基因型的苯作业人员WBC下降，苯染毒小鼠骨髓单个核细胞MDR1基因、P-gp表达下调，那么苯是否影响BMSCs MDR1基因和P-gp表达，并通过何种信号途径进行调节？本研究拟采用：1）HQ体外染毒兔BMSCs，观察BMSCs凋亡与BMSCs的MDR1基因、P-gp表达的相关性；2）NF-κB亚基p65的表达、磷酸化和转位对MDR1基因转录、P-gp表达的调控；3）MDR1基因过表达或表达沉默，对苯所致BMSCs凋亡的影响，初步阐明MDR1基因和P-gp是否依赖NF-κB信号途径参与苯的血液毒性，寻找慢性苯中毒治疗的新靶点。

中文关键词： 氢醌；骨髓间充质干细胞；多药耐药基因1；核转录因子-κB；

英文摘要： Over expression of P-gp encoded by MDR1 is associated with acting to pump the xenobiotics out of cells and protects cells from damage. Nuclear factor-kappa B (NF-κB) is a crucial transcriptional factor that plays a major role in regulating transcription of MDR1. Bone mesenchymal stem cells (BMSCs) modified geneticly can make the significant efficacy in many human disorders in various ways. We previously reported that people exposed to benzene with MDR1 3435TT genotype had the decreased white blood cell counts. The expression of MDR1 and P-gp on bone monocytes of C57BL/6 mice on gavage with benzene was down regulated. Based on these building blocks, we get ready to carry out the following three methods: 1) To detect the expression of MDR1 and P-gp on bone mesenchymal stem cells of rabbits after apoptosis induced by HQ treatment in vitro; 2) To analyze the regulation on MDR1 transcription and P-gp expression by phosphorylation, translocation and p65, p50 expression of NF-κB; 3) To investigate the influence of MDR1 over expression or gene silence on apoptosis induction of BMSCs. Our purpose is to illustrate the possible mechanism that whether MDR1 and P-gp get to involve in the benzene hematology toxicity with NF-κB signal transduction pathway. If the hypothesis is confirmed, one new strategy to control the chronic

英文关键词： Hydroquinone；Bone Mesenchymal stem cells；MDR1；NF-κB；