siRNA c60m3诱导慢粒白血病细胞系向红系分化的分子机制研究

项目名称： siRNA c60m3诱导慢粒白血病细胞系向红系分化的分子机制研究

项目编号： No.81200365

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 范翠青

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 诱导分化治疗是白血病治疗策略中最具潜能的方向之一。我们前期研究中，通过siRNA文库的筛选获得了能明显诱导慢粒K562细胞向红系分化的siRNA clone-60-mut-3（siRNA c60m3），此siRNA还抑制了细胞生长，但机制未明。因此，本项目拟在原有基础上，1）通过表达谱芯片与生物素标记的siRNA的方法，寻找此siRNA可能作用的下游靶基因；2）通过过表达及低表达候选基因，研究其对K562细胞生长、分化的影响，筛选出有功能作用的基因； 3）研究有功能作用的基因与红系分化关键转录因子如GATA1及分化信号通路中关键分子的相互作用，初步阐明基因作用机制。本研究将：明确siRNA c60m3 通过作用于靶基因诱导K562细胞向红系分化过程中所参与的信号通路及分子机制；力求发现慢性粒细胞白血病治疗的新靶点，为肿瘤的诱导分化治疗提供新的线索。

中文关键词： siRNA c60m3；红系分化；白血病；信号通路；

英文摘要： Differentiation induction therapy is one of the most promising strategy for leukemia therapy.?We previously carried out a high-throughput screening of erythroid differentiation-inducing siRNAs on human chronic myeloid leukemia K562 cells. siRNA c60m3 screened from the library was able to induce K562 cells differentiation along erythrocytic lineage significantly and also slow down cell proliferation rate. But the mechanism for erythroid differentiation induction is still unknown. Therefore, we will conduct further study in several aspects. Firstly, we will find the putative target genes of siRNA c60m3 by two approaches, which are microarray analysis of whole-genome gene expression profiling and biotinylated siRNA. Secondly, the effect of these genes on erythroid differentiation and cell growth of K562 cells will be validated in order to choose the functional genes. Finally, we will further study the interactions between these functional genes and key erythroid-specific transcription factors and major proteins in related signaling pathways, in order to elucidate the mechanism of gene functions. In summary, our study will clarify the mechanism of siRNA c60m3 effects on erythroid differentiation by acting on the downstream target genes.Moreover, this study aims to find new targets for the treatment of chronic my

英文关键词： siRNA c60m3；erythroid differentiation；leukemia；signaling pathway；