项目名称: 利用斑马鱼模型揭示造血干细胞归巢的细胞学过程及分子调控网络
项目编号: No.31301196
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: 董梅
作者单位: 中国科学院上海生命科学研究院
项目金额: 25万元
中文摘要: 分析造血干细胞归巢和迁移行为并揭示其分子调控机理对人类认识造血系统的稳态维持和优化造血干细胞移植相关治疗方案至关重要,然而相关研究一直受制于可视踪活体观察体系的缺失,机理尚不清楚。本项目拟利用斑马鱼通体透明的独特优势,建立造血干细胞与其微环境间相互作用的活体视踪体系并深入研究其细胞水平和分子水平上的调节机理。我们将利用特异影响造血干细胞归巢的斑马鱼整合素alpha4基因突变家系和标记干细胞血管微环境的转基因斑马鱼系,通过可诱导的整合素基因恢复表达和活体显微镜观察,在活体生物水平上揭示造血干细胞进入其微环境的整个动态过程。此外,我们将从已有的斑马鱼造血干细胞归巢异常突变库中找到3-4个影响干细胞迁移和归巢的新基因,并进一步观察分析其造血干细胞归巢行为和研究分子机理。我们的最终目标是建立造血干细胞归巢的活体分析系统,解析分子调控网络,并可能应用于筛选影响造血干细胞归巢和迁移的小分子化合物。
中文关键词: 归巢;造血干细胞;itga4;斑马鱼;
英文摘要: Study the homing process of hematopoietic stem cells (HSCs) and its regulatory mechanisms is essential for our understanding the homeostasis of hematopoietic system and for the improvement of clinical HSCs transplantation, however accumulating knowledge is limited due to the absence of live tracing system in vivo. In this proposal, we plan to take advantages of efficient transgenesis and transparence of zebrafish model to establish HSC homing tracing system in vivo and further investigate its mechanisms at cellular and molecular levels. From our accomplished forward genetics screen, we have acquired a mutant line with abrogation of zebrafish itga4 gene, which specifically affects HSCs homing process. We will trace the process of HSCs entering the niche by inducible ectopic ITGA4 expression within itga4 mutant lines and transgenic lines marking fluorescence niche/stem cells. Furthermore, we will discover 3-4 new genes affecting HSCs homing from our mutant pool, and then perform the analysis related homing behavior and molecular mechanisms. Our final goal is to build up HSC homing tracing systems in vivo,investigate regulatory network, and to facilitate the discovery of regulatory small molecules affecting HSC homing and migration.
英文关键词: homing;HSC;itga4;zebrafish;