ROLE OF C/EBPalpha AND MYELOPOIESIS

C/EBPα 和骨髓细胞生成的作用

• 批准号: 7569406
• 负责人: DANIEL G TENEN
• 金额: $ 41.28万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569406
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Binding; Blast Cell; Blood Cells; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Proteins; CEBPA gene; Cell physiology; Development; Family member; Fetal Liver; Funding; Gene Targeting; Goals; Grant; Granulopoiesis; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Knock-out; Knowledge; Lead; Mediating; Modeling; Myelogenous; Myelopoiesis; Nature; Pathway interactions; Regulation; Role; Staging; Stem Cell Development; Testing; Time; chromatin immunoprecipitation; cytokine; granulocyte; in vivo; insight; leukemia; leukemogenesis; macrophage; member; progenitor; self-renewal; transcription factor

Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding and treatments of various blood diseases, including leukemias. The long range goals are to further our understanding of the mechanisms involved in myelopoiesis and leukemia by understanding the transcription factors which regulate myeloid development from stem cells. The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBP alpha) is required for differentiation of normal myeloid blasts and disrupted through multiple mechanisms in Acute Myeloid Leukemia (AML). Conditional knockout models demonstrate that loss of C/EBP alpha leads to increased self-renewal and repopulating ability of fetal liver hematopoietic stem cells (HSC), as well as a block in differentiation at a distinct stage of granulocytic differentiation. Over the next 5 years, we propose to extend the study of this critical transcription factor in hematopoietic stem cells. We therefore propose the following Specific Aims: (1) What is the role of C/EBP alpha with respect to numbers and function of adult HSC? (2) What is the role of cytokines on C/EBP family member expression and granulopoiesis? (3) How does C/EBPa regulate Bmi-1 and affect HSC function? These studies will lead to new insights into the role of this transcription factor in HSC and progenitor function, which is relevant to the understanding of normal hematopoietic differentiation and leukemogenesis.

了解血细胞正常发育的机制将带来新的发现 了解和治疗各种血液疾病，包括白血病。长期目标是 通过了解骨髓生成和白血病的机制，进一步了解 调节干细胞骨髓发育的转录因子。转录因子CCAAT 增强子结合蛋白 α (C/EBP α) 是分化正常髓系母细胞和 急性髓系白血病 (AML) 中的多种机制受到破坏。条件淘汰模型 证明 C/EBP α 的缺失会增加胎儿肝脏的自我更新和再生能力 造血干细胞 (HSC)，以及粒细胞特定阶段的分化受阻 差异化。在接下来的 5 年里，我们建议扩大对这一关键转录因子的研究 造血干细胞。因此，我们提出以下具体目标： (1) C/EBP α 对于成人 HSC 的数量和功能有何作用？ (2)细胞因子对C/EBP家族成员表达和粒细胞生成的作用是什么？ (3)C/EBPα如何调节Bmi-1并影响HSC功能？ 这些研究将为该转录因子在 HSC 和祖细胞中的作用提供新的见解 功能，这与理解正常造血分化和白血病发生有关。