Zfx, A Novel Transcriptional Regulator of Hematopoiesis

Zfx，一种新型造血转录调节因子

• 批准号: 7799220
• 负责人: Boris Reizis
• 金额: $ 38.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799220
• 关键词: Adult; Blood; Bone Marrow; Cell Cycle; Cells; Development; Erythroid; Gene Targeting; Growth and Development function; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Immature Lymphocyte; Impairment; In Vitro; Life; Lymphocyte; Lymphopoiesis; Maintenance; Mediating; Molecular; Mus; Myelogenous; Pathway interactions; Phenotype; Repression; Role; Specificity; Staging; System; T-Lymphocyte; Testing; Transcription Coactivator; Zinc Fingers; base; gene repression; inhibitor/antagonist; novel; overexpression; progenitor; programs; research study; self-renewal; stem cell population; transcription factor

DESCRIPTION (provided by applicant): Mammalian hematopoiesis is based on the activity of hematopoietic stem cells (HSC) that undergo continuous self-renewal throughout the adult life. The long-term maintenance of bone marrow HSC appears to be regulated by highly specific transcriptional mechanisms that remain largely unknown. The progeny of self-renewing HSC initiate ordered differentiation programs that give rise to all blood lineages. In particular, the development of B and T lymphocytes involves a massive proliferative expansion of immature precursors. Both HSC self-renewal and lymphocyte expansion appear exquisitely sensitive to elevated levels of the cell] cycle inhibitor p16lnk4a, which is actively repressed by poorly defined molecular pathways. Our studies of hematopoiesis focused on Zfx, an evolutionarily conserved zinc finger-containing transcription factor. In preliminary experiments, inactivation of murine Zfx in the hematopoietic system leads to a specific loss of adult bone marrow HSC population. In addition, the expansion of immature B and T lymphocytes was severely impaired. Preliminary expression analysis suggests that these phenotypes might be caused by the overexpression of p16lnk4a in the absence of Zfx. Therefore, Zfx might represent an essential and specific positive regulator of HSC self-renewal and of immature lymphocyte expansion upstream of p16lnk4a. To test this hypothesis, three Specific Aims are proposed. First, the role of Zfx in HSC self-renewal will be characterized at the functional level. Second, early development and growth of Zfx-deficient lymphocytes will be investigated. Third, the molecular basis of Zfx activity will be established through the identification and functional analysis of its target genes in hematopoietic cells. These studies might identify novel molecular mechanisms that facilitate the maintenance of HSC and of immature lymphocytes, possibly through the repression of p16lnk4a.

描述（由申请人提供）：哺乳动物的造血作用基于造血干细胞（HSC）的活性，造血干细胞在整个成年过程中不断进行自我更新。骨髓 HSC 的长期维持似乎受到高度特异性的转录机制的调节，但这些机制在很大程度上仍然未知。自我更新的 HSC 后代启动有序分化程序，产生所有血统。特别是，B 和 T 淋巴细胞的发育涉及未成熟前体细胞的大规模增殖扩张。 HSC 的自我更新和淋巴细胞的扩增似乎对细胞周期抑制剂 p16lnk4a 水平的升高非常敏感，而 p16lnk4a 会受到定义不明确的分子途径的积极抑制。我们对造血作用的研究主要集中在 Zfx，一种进化上保守的含锌指转录因子。在初步实验中，小鼠造血系统中 Zfx 的失活导致成年骨髓 HSC 群体的特定损失。此外，未成熟B和T淋巴细胞的扩增受到严重损害。初步表达分析表明，这些表型可能是由于在 Zfx 缺失的情况下 p16lnk4a 的过度表达引起的。因此，Zfx 可能代表 HSC 自我更新和 p16lnk4a 上游未成熟淋巴细胞扩增的重要且特异的正调节因子。为了检验这一假设，提出了三个具体目标。首先，Zfx 在 HSC 自我更新中的作用将在功能层面上进行表征。其次，将研究 Zfx 缺陷淋巴细胞的早期发育和生长。第三，通过造血细胞中Zfx靶基因的鉴定和功能分析，建立Zfx活性的分子基础。这些研究可能会发现新的分子机制，可能通过抑制 p16lnk4a 来促进 HSC 和未成熟淋巴细胞的维持。