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: 7105654
• 负责人: Graham John Lieschke
• 金额: $ 26.37万
• 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/7105654
• 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）： 先天性髓样衰竭综合征是一群与大量发病相关的罕见遗传疾病。尽管最近了解了这些疾病子集的遗传基础，但其他疾病的分子发病机理仍然未知。我们的目标是在模型脊椎动物（斑马鱼）中使用远期遗传方法来开发遗传性髓样衰竭的动物模型。这些模型的全面表征以及它们的遗传阐明将导致有关这些疾病的分子发病机理的新知识，从而有助于其诊断，治疗以及可能的预防。一组具有髓样衰竭的斑马鱼突变体是由乙硝基乙酸诱变和遗传筛查产生的。迄今为止，已经回收了十个稳定的突变体系（恢复率为83％），> 15个在各个恢复阶段。该项目的目的是（1）使用显微镜，组织学，整个原位杂交基因表达分析和移植测定法描述突变体； （2）将所有突变体放在斑马鱼基因组图上，并将其在其各自的连锁组中； （3）在其表型的特殊生物学利益方面优先考虑突变体的位置6。在确定了这些特别有趣的髓样失败突变体的遗传基础之后，我们将更好地理解这些基因在髓样细胞发育的分子和细胞机制中的功能。由于产生突变体的无偏见，因此有些人应揭示出对先天性髓样衰竭原因的全新见解。其他发现在已经与骨髓相关的基因的新突变的其他突变体可能会揭示对髓样细胞疾病的分子发病机理和正常髓样细胞增殖，分化，生存和功能的新见解。更好地了解正常的髓样细胞发育也将有助于了解脊髓增生性疾病和白血病疾病中这些过程失调的基础。