基于Irf8的突变体建立斑马鱼白血病模型

项目名称： 基于Irf8的突变体建立斑马鱼白血病模型

项目编号： No.31301198

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 李礼

作者单位： 西南大学

项目金额： 23万元

中文摘要： 白血病是一类极其严重的血液系统疾病，具有较高的致死率，危害极大。白血病的发生发展是白细胞异常发育的结果，因此研究白细胞的发育机理并寻找能够治疗白血病的新型小分子药物具有极大的社会意义。本项目通过TALEN技术构建了白细胞发育缺陷的irf8突变体。初步研究结果提示irf8突变体的纯合子可以存活，并表现出髓系白细胞发育的缺陷，主要为粒细胞的大量增生。Irf8突变体的表型与临床的髓系白血病表型相似，提示了基于irf8突变体的纯合子建立斑马鱼髓系白血病的可能性。同时，结合已有的基于pu.1G242D突变体构建的M2型髓系白血病模型，和能够活体实时观测白细胞发育状况的Tg(coro1a:eGFP;lyz:Dsred)，高通量的小分子化合物筛选势在必行。本研究将为进一步解析白细胞发育和白血病发生发展的机理并寻找治疗白血病的有效小分子药物提供富有价值信息和参考。

中文关键词： Irf8；Mertk；髓系细胞；白血病；斑马鱼

英文摘要： Leukemia is a harmful disease resulted from the defect of leukocytes development or leukopoiesis. Although the mechanism of leukopoiesis and leukemia formation is being exploited continously until now, it has not been well dissected yet, which prevents the progress in the cure of leukemia. Up to now, the best way to treat leukemia is bone marrow transplantation, which is limited by the requirement of the blood type matchment and repression of immunal rejection as well as high cost unfortunately. As a result, chemical drug treatment is still the first choice in clinical. In order to discover more effective chemical drugs and explore the molecular mechanism inside,our lab decided to establish the zebrafish leukemia especially myeloid leukemia model based on the myelopoiesis defect mutant, which will be utilized for the High Throughout Screening (HTS) of the chemical drugs useful for leukemia treatment. With this as the goal, our lab firstly knocked out irf8, a well known factor functioning in the myeloid cell development and myeloid leukemia formation, genetically in zebrafish by TALEN. We successfully obtained the germ-transmition mutant fish. The preliminery data indicated that the irf8 mutant homozygous could survive beyond adult and manifested disturbed myeloid cells type, such as the expand of neutrophils and

英文关键词： Irf8；Mertk；myeloid cells；leukemia；zebrafish