用于高通量药物筛选的斑马鱼c-myb过表达白血病模型的建立

项目名称： 用于高通量药物筛选的斑马鱼c-myb过表达白血病模型的建立

项目编号： No.81470335

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： 张文清

作者单位： 南方医科大学

项目金额： 170万元

中文摘要： 基于斑马鱼疾病模型的药物筛选已经成为新药发现的核心技术。c-myb作为重要的转录因子参与造血发育和分化过程，其过表达缺陷会导致人髓系或淋系白血病。但目前还缺少c-myb白血病动物模型。 我们获得一个c-myb过表达转基因斑马鱼，发现具有以下表型：①早期髓系祖细胞分化异常，粒细胞明显增生；②早期淋系缺陷，晚期恢复；③成鱼肾脏血中粒系增多。④1.5年龄斑马鱼中部分出现淋巴细胞全身浸润。总体表型类似人慢性中性粒细胞白血病/非典型慢性髓系白血病（CNL/ACML），其中部分可进展为急性髓系白血病（AML）或急性淋系白血病（ALL）。我们假设该c-myb转基因斑马鱼是一种特殊类型的白血病模型，但其与人CNL/ACML的相似性、进展为AML或ALL的关键因素及动物模型建立等科学问题仍需解决。 本项目拟进行：①表型鉴定；②白血病模型的建立及其发病机制、分型和临床比对；③已知药物对斑马鱼模型的药理学验证。

中文关键词： 斑马鱼；白血病；c-myb；疾病模型；药物筛选

英文摘要： Drug screening based on the zebrafish animal model has become a core technology to discover new drugs. c-Myb as an important transcription factor is involved in hematopoietic development and differentiation process, and its expression defects can directly lead to human myeloid or lymphoid leukemia. However, none ideal zebrafish model was provided to have a deep insight of leukemia caused by c-myb. We've got a c-myb over expression transgenic zebrafish, phenotypic preliminary analysis found that: ① The c-myb over expression fish had abnormal myeloid progenitor cell differentiation and granulocyte hyperplasia in the early stage; ② Lymphocytes defect in the early stage and late recovery; ③ The percentage of granulocyte in the kidney marrow is significant higher in the c-myb over expression transgenic zebrafish than in wild-types. ④ Part of 1.5 year old c-myb over expression zebrafish show a lymphocytic infiltrates phenotype. We assume that c-myb overexpression zebrafish is likely to be a chronic neutrophilic leukemia/atypical chronic myeloid leukemia (CNL/ACML) animal model, and some of them can progress to acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL). But how similarity between c-myb transgenic zebrafish model and human disease, what are the key factors in the progress of CNL/ACML upgrade to AML or ALL still need to be solved. In this proposed research, we aim (1) to identify phenotype of the c-myb over expression fish; (2) to establish an ideal zebrafish leukemia model and investigate its pathogenesis, typology, clinic data comparison; and (3) to verify the model using some known clinic drugs. These studies will further deepen our mechanistic understanding of myeloid lineage development in general and the CNL/ACML animal models will provide new molecular markers for early diagnosis, prognosis, treatment effect evaluation and new strategies for drug discovery and therapeutic treatments.

英文关键词： zebrafish;leukemia;c-myb;disease model;drug screening