MOLECULAR BIOLOGY OF HUMAN MYELOID DIFFERENTIATION

人类骨髓分化的分子生物学

• 批准号: 2090454
• 负责人: DANIEL G TENEN
• 金额: $ 29.33万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2090454
• 关键词: CD antigens; DNA binding protein; DNA footprinting; HeLa cells; RNase protection assay; antisense nucleic acid; cell differentiation; embryonic stem cell; flow cytometry; gene expression; genetic promoter element; genetic regulation; genetically modified animals; hematopoiesis; human tissue; laboratory mouse; leukocyte adhesion molecules; messenger RNA; myelocyte; myeloid stem cell; northern blottings; polymerase chain reaction; transcription factor

Proliferating bone marrow precursors ("stem cells") differentiate to produce mature hematopoietic cells. The molecular controls governing commitment to and differentiation of the myeloid (granulocyte/monocyte) lineage, the lineage in which a block in differentiation results in over 90% of acute leukemias in adults, have not been fully elucidated. One hypothesis is that the expression of lineage specific transcription factors play a major role in commitment and differentiation. The overall goal of this continuation proposal is to continue to study how factors such as PU.1 regulate the expression of the gene encoding CD11b (Mac-1 alpha), a cell surface adhesion protein which is specifically expressed in myeloid cells and strongly up-regulated during the course of human myeloid differentiation as a model to understand (1) commitment of normal hematopoietic precursors to the myeloid lineage; and (2) the process of normal myeloid maturation from myeloid blasts to mature myeloid cells, a process which is blocked in acute myelogenous leukemia (AML). Therefore, in order to further characterize the molecular mechanisms of the regulation and expression of the CD11b gene in myeloid cells, and the role of the PU.1 transcription factor in myeloid commitment and differentiation, we propose the following specific aims: (1) To determine if the PU.1 and Sp1 transcription factors function as important determinants of the myeloid specific expression of the CD11b promoter in ES cells and transgenic mice; (2) To determine the expression pattern of the PU.1 protein during myeloid commitment, and the molecular controls of the regulation of PU.1 expression; and (3) T determine the importance of the PU.1 factor in vivo for CD11b expression, myeloid lineage commitment, and differentiation.

增殖的骨髓前体（“干细胞”）分化为 产生成熟的造血细胞。 分子控制 对髓样的承诺和分化（粒细胞/单核细胞） 谱系，分化块导致过度的谱系 成人90％的急性白血病尚未完全阐明。 一 假设是谱系特定转录的表达 因素在承诺和差异化中起着重要作用。 该延续建议的总体目标是继续学习 PU.1等因素如何调节基因编码的表达 CD11b（Mac-1 alpha），一种细胞表面粘附蛋白，是 特别在髓样细胞中表达，并在 人类髓样分化为理解的模型的过程（1） 正常造血前体对髓样谱系的承诺；和 （2）正常髓样成熟的过程从髓样爆炸到 成熟的髓样细胞，该过程被阻断 白血病（AML）。 因此，为了进一步表征 CD11b基因在髓样细胞中的调节和表达， PU.1转录因子在髓样承诺中的作用和 差异化，我们提出以下特定目的：（1） 确定PU.1和SP1转录因子是否起作用 CD11b启动子在 ES细胞和转基因小鼠； （2）确定 髓样承诺期间的PU.1蛋白质和分子对照 PU.1表达的调节； （3）t确定重要性 CD11b表达的pu.1因子在体内的因子，髓样谱系 承诺和差异化。