利用斑马鱼模型研究kri1蛋白在造血干祖细胞发育中的作用

项目名称： 利用斑马鱼模型研究kri1蛋白在造血干祖细胞发育中的作用

项目编号： No.31301209

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： 井长斌

作者单位： 中国科学院上海生命科学研究院

项目金额： 21万元

中文摘要： 造血干细胞是机体中所有成熟血细胞的源头。造血干细胞的发育、自我更新以及分化的机制是受到严格精确调控的，如果这种调控机制出现异常会产生严重的血液疾病，如贫血或白血病。为了充分阐述这一调控网络，我们利用斑马鱼模式生物开展了定向造血表型的遗传学筛选。在突变库中我们发现了家系ldd499表现为造血干祖细胞的减少。目前已经完成对突变体表型的分析和定位克隆，并确定是由于kri1基因的失活所造成的造血干祖细胞的减少表型。本课题的目标是揭示kri1蛋白调控造血干细胞发育的机理。我们将一方面利用斑马鱼模型明确kri1失活对造血干细胞发育的细胞学和发育生物学水平的影响，另一方面在分子水平阐述kri1调控造血干祖细胞发育的机制，希望此项研究为诊治人类疾病提供重要理论依据。

中文关键词： 造血干祖细胞；kri1l；核糖体合成；自噬；PERK

英文摘要： Hematopoietic stem cells (HSCs) give rise to all the lineages of blood cells in human body. The development, self-renewal and differentiation of HSCs are strictly and accurately controlled in embryonic development and also in adulthood. Disordered regulatory mechanisms results in types of blood disease, like anemia or leukemia. To elucidate such important regulatory network, we performed a large-scale forward genetic screen with HSC markers on zebrafish model organism. We found ldd499 mutants zebrafish were overall morphological normal, but carrying HSCs increasing phenotype as homozygotes. Through genetic mapping and subsequent validation, we confirmed ldd499 phenotype is due to the loss of kri1 protein, caused by nonsense mutation in its genomic coding region. This project aims to understand Kri1-mediated regulation on HSCs development. With the combination of genetic and developmental biology approaches, we plan to study on the role kri1 in HSCs determination. Furthermore, we will perform molecular and biochemical experiments to reveal its mechanism. Through genomic analysis on human patients blood samples, certain type of anemia or leukemia will be linked with kri1-regulatory mechanism and with potential clinical applications.

英文关键词： Hematopoietic stem cells；kri1l；ribosome biogenesis；autophagy；PERK