The role of E47 in uncommitted hematopoietic progenitors

E47 在未定型造血祖细胞中的作用

• 批准号: 7647823
• 负责人: Lisa Borghesi
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647823
• 关键词: Address; Adult; Alleles; Animals; Antigen Receptors; Biological Assay; Biological Models; Blood; Bone Marrow; Bone Marrow Cells; Cell Count; Cell Cycle; Cell Proliferation; Cells; Common Lymphoid Progenitor; DNA Sequence Rearrangement; Data; Defect; Differentiation Antigens; E protein; Equilibrium; Event; Exhibits; Gene Targeting; Genes; Genetic; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterozygote; Homeostasis; Immune system; Individual; Knockout Mice; Life; Link; Lymphocyte; Lymphoid; Maintenance; Malignant Neoplasms; Molecular; Multipotent Stem Cells; Mus; Natural regeneration; Pathway interactions; Phase; Play; Population; Production; Protein Family; Residual state; Role; Seeds; Staging; Stem cells; T-Cell Development; T-Lymphocyte; Testing; Tissues; VDJ Recombinases; Wild Type Mouse; Work; design; exhaustion; functional loss; gain of function; helix-loop-helix protein E47; in vivo; inhibitor/antagonist; insight; loss of function; member; oncoprotein p21; pathogen; prevent; progenitor; public health relevance; recombinase; reconstitution; residence; self-renewal; transcription factor

DESCRIPTION (provided by applicant): Bone marrow hematopoietic stem cells continually seed the blood lineages throughout adult life. E47 is a major transcription factor whose activity is critical for the progression of uncommitted hematopoietic progenitors to the lymphoid lineages. Perturbations in E47 expression are also associated with blood cancers. We have found that mice lacking E47 have a profound depletion of bone marrow multipotent progenitors as well downstream lineage restricted populations. Primitive precursors from E47 deficient mice exhibit heightened proliferative activity but decreased expression of key markers associated with differentiation. Reciprocal gain of function and loss of function studies identify two key genes as candidate E47 targets: the cell cycle regulator p21 and the transcriptional regulator Ikaros. Here, we propose to establish the mechanistic relationship between E47 and these two factors in primary bone marrow precursor subsets. In Aim 1, we focus on the proliferative defect and determine if E47 is a critical regulator of the balance between stem cell proliferation and self-renewal. In Aim 2, we examine whether E47 and p21 collaborate in the same genetic pathway to regulate stem cell proliferation. In Aim 3, we determine if Ikaros is the essential E47 target gene that regulates the differentiation of primary multipotent progenitors to the lymphoid lineages. Together, these aims address the molecular mechanisms that regulate the functional integrity of stem cells during lymphoid lineage progression. This work will provide new information about the molecular events that control stem cell integrity, and will provide key insight into the mechanisms by which dysregulation of E47 activity contributes to cancers of lymphoid origin. Public Health Relevance: The immune system is capable of responding to a vast array of potential pathogens. This is accomplished in part through the production of B and T lymphocytes. Our studies are aimed at elucidating the factors that regulate the functional integrity of hematopoietic stem cells during progression to the lymphocyte lineages.

描述（由申请人提供）：骨髓造血干细胞在整个成人生活中不断播种血统。 E47是主要的转录因子，其活性对于不承诺的造血祖细胞向淋巴样谱系的发展至关重要。 E47表达中的扰动也与血液癌有关。我们发现缺乏E47的小鼠对骨髓多能祖细胞以及下游谱系限制性人群的耗尽。来自E47缺乏小鼠的原始前体表现出增强活性，但与分化相关的关键标记表达降低。功能和功能研究丧失研究的相互增益将两个关键基因识别为候选E47靶标：细胞周期调节剂p21和转录调节剂Ikaros。在这里，我们建议在原代骨髓前体亚群中建立E47与这两个因素之间的机械关系。在AIM 1中，我们专注于增殖缺陷，并确定E47是否是干细胞增殖与自我更新之间平衡的关键调节剂。在AIM 2中，我们检查了E47和P21是否在相同的遗传途径中合作以调节干细胞增殖。在AIM 3中，我们确定IKAROS是否是调节一级多能祖细胞与淋巴样谱系的分化的必不可少的E47靶基因。这些目的共同解决了调节淋巴谱系过程中干细胞功能完整性的分子机制。这项工作将提供有关控制干细胞完整性的分子事件的新信息，并将为E47活性失调的机制提供关键的见解，从而有助于淋巴机的癌症。公共卫生相关性：免疫系统能够应对各种潜在病原体。这部分是通过生产B和T淋巴细胞来完成的。我们的研究旨在阐明调节造血干细胞在淋巴细胞谱系过程中的功能完整性的因素。