Congenital myeloid failure syndromes in mutant zebrafish

突变斑马鱼的先天性骨髓衰竭综合征

• 批准号: 7135807
• 负责人: Graham John Lieschke
• 金额: $ 27万
• 依托单位: WALTER AND ELIZA HALL INST MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135807
• 关键词: animal genetic material tag; apoptosis; cell differentiation; cell proliferation; cell transplantation; congenital blood disorder; developmental genetics; gene expression profiling; genetic models; genetic regulation; hematopoietic tissue transplantation; high performance liquid chromatography; immunocytochemistry; in situ hybridization; model design /development; molecular cloning; molecular pathology; mutant; myeloid stem cell; nitrosourea; phenotype; restriction fragment length polymorphism; zebrafish

DESCRIPTION (provided by applicant): Congenital myeloid failure syndromes are a heterogeneous group of rare hereditary disorders associated with considerable morbidity. Despite recent insights into the genetic basis for a subset of these disorders, the molecular pathogenesis of others remains unknown. Our goal is to use a forward genetic approach in a model vertebrate, the zebrafish, to develop animal models of hereditary myeloid failure. Comprehensive characterization of these models, coupled with their genetic elucidation, will lead to new knowledge about the molecular pathogenesis of these disorders, aiding their diagnosis, treatment and possibly prevention. A group of zebrafish mutants with myeloid failure has been generated by ethylnitrosourea mutagenesis and genetic screening. Ten stable mutant pedigrees have been recovered to date (a recovery rate of 83%), and >15 more are at various stages of recovery. This project aims to (1) characterize the mutants descriptively using microscopy, histology, whole mount in situ hybridization gene expression analysis, and transplantation assays; (2) position all the mutants on the zebrafish genome map in their respective linkage groups; (3) positionally clone 6 of the mutants, prioritized for the particular biological interest of their phenotypes. Having identified the genetic basis of these particularly interesting myeloid-failure mutants, we will better understand the function of these genes in the molecular and cellular mechanisms of myeloid cell development. Because of the unbiased nature of generating the mutants, some of them are expected to reveal completely new insights into the causes of congenital myeloid failure. Other mutants, found to have novel mutations in genes already associated with myelopoiesis, will likely reveal new insights into the molecular pathogenesis of myeloid cell disease and normal myeloid cell proliferation, differentiation, survival and function. A better understanding of normal myeloid cell development will also help understand the basis for the dysregulation of these processes in myeloproliferative and leukemic diseases.

描述（由申请人提供）： 先天性骨髓衰竭综合征是一组异质性罕见遗传性疾病，发病率相当高。尽管最近对这些疾病的一部分的遗传基础有了深入的了解，但其他疾病的分子发病机制仍然未知。我们的目标是在模型脊椎动物斑马鱼中使用正向遗传方法来开发遗传性骨髓衰竭的动物模型。这些模型的综合表征，加上它们的基因阐明，将带来关于这些疾病的分子发病机制的新知识，有助于它们的诊断、治疗和可能的预防。通过乙基亚硝基脲诱变和遗传筛选产生了一组骨髓衰竭的斑马鱼突变体。迄今为止，已恢复了 10 个稳定的突变体谱系（恢复率为 83%），还有超过 15 个处于不同的恢复阶段。该项目的目的是（1）利用显微镜、组织学、整体原位杂交基因表达分析和移植测定来描述性地表征突变体； (2) 将所有突变体在斑马鱼基因组图谱上定位在各自的连锁群中； (3) 按位置克隆 6 个突变体，优先考虑其表型的特定生物学意义。在确定了这些特别有趣的骨髓衰竭突变体的遗传基础后，我们将更好地了解这些基因在骨髓细胞发育的分子和细胞机制中的功能。由于产生突变体的公正性，其中一些突变体有望揭示先天性骨髓衰竭原因的全新见解。其他突变体被发现在与骨髓生成相关的基因中具有新的突变，可能会揭示对骨髓细胞疾病和正常骨髓细胞增殖、分化、存活和功能的分子发病机制的新见解。更好地了解正常骨髓细胞的发育也将有助于了解骨髓增生性疾病和白血病疾病中这些过程失调的基础。