The Role of Geminin in Hematopoiesis

Geminin 在造血中的作用

• 批准号: 7689196
• 负责人: THOMAS J MCGARRY
• 金额: $ 19.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689196
• 关键词: Affect; Animals; Antibodies; Apoptosis; Binding; Biological Process; Blood Cells; Blood Circulation; Bone Marrow; Breeding; Bromodeoxyuridine; Cell Cycle; Cell Cycle Arrest; Cell Differentiation process; Cell division; Cells; Choices and Control; Commit; Complete Blood Count; DNA; DNA biosynthesis; Development; Dysmyelopoietic Syndromes; Embryo; Equilibrium; Erythrocytes; Erythroid; Exons; Exploratory/Developmental Grant; Fanconi' s Anemia; Flow Cytometry; G2 Phase; GMNN gene; Geminin; Gene Targeting; Genes; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic System; Hematopoietic stem cells; Homeobox; Infiltration; Inner Cell Mass; Interferons; Knock-out; Label; Laboratories; Lead; Learning; Leukocytes; Life; Lymphoma; Maintenance; Malignant Neoplasms; Marrow; Measures; Megakaryocytes; Methylcellulose; Monitor; Mus; Myelogenous; Oncogenic; Organ; Pathway interactions; Pattern; Peripheral; Persons; Phenotype; Physiologic pulse; Ploidies; Pluripotent Stem Cells; Poly I-C; Predisposition; Production; Proliferating; Proteins; Proto-Oncogene Protein c-kit; Role; Site; Staining method; Stains; Stem cells; T-Lymphocyte; TP53 gene; Testing; Time; Tumor Suppressor Proteins; Undifferentiated; annexin A5; chromatin remodeling; cytopenia; design; genetic regulatory protein; homeodomain; interest; leukemia; leukemia/lymphoma; neoplastic cell; peripheral blood; pluripotency; prevent; progenitor; promoter; recombinase; research study; response; transcription factor

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) in the bone marrow supply the circulation with mature blood cells throughout life. Division of the HSCs both replenishes their own numbers and provides committed progenitor cells that give rise to the erythrocyte, leukocyte, and megakaryocyte lineages. Progenitor cells undergo a limited number of divisions then differentiate into mature blood cells. Progenitor cell division and differentiation must be carefully balanced in order to provide the correct numbers and proportions of mature cells. Imbalances between proliferation and differentiation underlie common hematological problems like leukemia, lymphoma, and myelodysplastic syndromes. Despite their obvious importance, the mechanisms that control the choice between continued cell division and terminal differentiation are largely unknown. This project will examine the role of the regulatory protein Geminin in the proliferation and differentiation of hematopoietic cells. Geminin is required for pluripotency and is thought to maintain dividing cells in an undifferentiated state. Geminin is a bi-functional protein that controls the extent of DNA replication and inhibits homeodomain (Hox) transcription factors that are known to be crucial regulators of hematopoiesis. Geminin knockdown activates the Fanconi Anemia pathway, and over- expression of the replication factor inhibited by Geminin, Cdt1, in p53-/- T cells accelerates the development of lymphoblastic lymphoma. We are using a conditional knockout strategy to investigate the role of Geminin in definitive hematopoiesis. Gene-targeted mice, in which LoxP sites flank the essential exons of the Geminin gene, are being bred to mice that express Cre recombinase under the control of the interferon-inducible Mx-1 promoter. These mice will be treated with polyinosine- polycytidine (poly I:C) to induce Cre recombinase and delete the Geminin gene in hematopoietic cells. We will determine how Geminin loss affects the pattern of cell division and differentiation in the bone marrow, how Geminin regulates the cell cycle of hematopoietic cells, and whether Geminin suppresses the development of leukemias or lymphomas. We hope to gain a more complete understanding of normal hematopoiesis and identify a new target for therapy of hematological malignancies. PROJECT NARRATIVE Stem cells in the bone marrow continually divide throughout a person's life in order to produce mature blood cells. Problems in the division or the maturation of the growing blood cells give rise to leukemia and lymphoma, two of the most common cancers. This project examines the role of the protein Geminin in controlling blood cell development.

描述（由申请人提供）：骨髓中的造血干细胞（HSC）在整个生命周期中为循环提供成熟的血细胞。HSC的分裂既增加了它们自身的数量，又提供了定向祖细胞，这些定向祖细胞产生红细胞、白细胞和巨核细胞谱系。祖细胞经历有限数量的分裂，然后分化成成熟的血细胞。祖细胞分裂和分化必须仔细平衡，以提供正确数量和比例的成熟细胞。增殖和分化之间的不平衡是常见血液学问题的基础，如白血病、淋巴瘤和骨髓增生异常综合征。尽管它们的重要性显而易见，但控制细胞持续分裂和终末分化之间选择的机制在很大程度上是未知的。本研究将探讨调控蛋白Geminin在造血细胞增殖和分化中的作用。Geminin是多能性所必需的，并且被认为维持分裂细胞处于未分化状态。Geminin是一种双功能蛋白质，其控制DNA复制的程度并抑制同源结构域（Hox）转录因子，已知同源结构域（Hox）转录因子是造血的关键调节因子。Geminin敲低激活Fanconi贫血通路，并且在p53-/- T细胞中由Geminin抑制的复制因子Cdt 1的过度表达加速淋巴母细胞性淋巴瘤的发展。我们正在使用条件性基因敲除策略来研究Geminin在确定性造血中的作用。基因靶向小鼠，其中LoxP位点侧翼的Geminin基因的基本外显子，正在培育的小鼠表达Cre重组酶的干扰素诱导型Mx-1启动子的控制下。这些小鼠将用聚肌苷-聚胞苷（poly I：C）处理以诱导Cre重组酶并删除造血细胞中的Geminin基因。我们将确定Geminin损失如何影响骨髓中细胞分裂和分化的模式，Geminin如何调节造血细胞的细胞周期，以及Geminin是否抑制白血病或淋巴瘤的发展。我们希望能对正常造血有更全面的了解，并为恶性血液病的治疗寻找新的靶点。骨髓中的干细胞在人的一生中不断分裂，以产生成熟的血细胞。生长中的血细胞的分裂或成熟出现问题会引起白血病和淋巴瘤，这是两种最常见的癌症。该项目研究蛋白质Geminin在控制血细胞发育中的作用。