SPI-1 AND SPI-B AND HEMATOPOIETIC DEVELOPMENT

SPI-1 和 SPI-B 与造血发育

• 批准号: 2229252
• 负责人: M. CELESTE SIMON
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2229252
• 关键词: carcinogenesis; cell type; developmental genetics; erythroleukemia; gene expression; gene mutation; genetic library; genetic recombination; genetic regulation; genetically modified animals; hematopoiesis; hematopoietic stem cells; laboratory mouse; leukemia; loss of heterozygosity; molecular cloning; molecular oncology; neoplasm /cancer genetics; nucleic acid hybridization; polymerase chain reaction; protooncogene; tissue /cell culture; transcription factor

Macrophages play an essential role in host defense: they ingest and kill pathogens, process and present antigens to lymphocytes, and secrete functionally diverse cytokines. Patients lacking healthy phagocytic cells, such as macrophages and neutrophils, exhibit a lethal susceptibility to infection by microbes. Monocytes display an important cytotoxic activity for tumor cells in breast, lung, and gastrointestinal cancers. However, little is known about the molecular mechanisms controlling myeloid cell (macrophage and neutrophil) development. The proto-oncogene Spi-1 and a related gene, Spi-B, are the first examples of lineage-restricted transcription factors implicated in gene regulation in myeloid cells. Using a genetic approach, involving mouse embryonic stem cells and mutant myeloid cell lines, we will assess the role of Spi-1 and Spi-B in myeloid cell development and gene expression. We will also learn what roles they play in the production of other hematopoietic cells. Spi-1 causes erythroleukemias when aberrantly expressed in red cell precursors. We will show which known myeloid- specific genes are downstream targets for Spi-1 and ascertain if they are involved in erythroleukemogenesis. We will identify novel Spi-1-regulated genes and determine if they also function in Spi-1- induced oncogenesis. We will assess the regulation of a myeloid- specific gene, the c-fes proto-oncogene, by Spi-1 and Spi-B. We hope to identify and clone genes encoding other myeloid-specific nuclear regulatory proteins. The discovery of additional lineage- restricted myeloid transcription factors is necessary for a complete understanding of myeloid cell gene expression. These experiments are critical to a better description of the molecular events that produce myeloid cells from hematopoietic progenitor cells. The proposed studies are relevant both to normal hematopoietic (and specifically myeloid cell) development and to the molecular pathogenesis of hematopoietic neoplasia.

巨噬细胞在宿主防御中起着至关重要的作用：他们摄入和 杀死病原体，过程和抗原淋巴细胞，以及 分泌功能多样的细胞因子。缺乏健康的患者 吞噬细胞（例如巨噬细胞和中性粒细胞）表现出A 微生物感染的致命敏感性。单核细胞显示 乳房中肿瘤细胞的重要细胞毒性活性，肺， 和胃肠道癌。但是，关于 控制髓样细胞的分子机制（巨噬细胞和 中性粒细胞的发育。原始癌基因SPI-1和相关的 基因，SPI-B是谱系限制的第一个例子 与基因调节有关的髓样的转录因子 细胞。使用遗传方法，涉及小鼠胚胎茎 细胞和突变的髓样细胞系，我们将评估 SPI-1和SPI-B在髓样细胞发育和基因表达中。我们 还将了解他们在其他人的生产中扮演的角色 造血细胞。 SPI-1在异常时会引起红血病 在红细胞前体中表达。我们将展示哪种髓样 特定基因是SPI-1的下游靶标，并确定是否是否 它们参与了红血球发生。我们将确定小说 SPI-1调节的基因并确定它们是否也在SPI-1-中起作用 诱导的肿瘤发生。我们将评估髓样的调节 - 特定基因，即Spi-1和Spi-B的C-FES原型癌基因。我们 希望识别和克隆基因编码其他髓样特异性 核调节蛋白。发现其他血统 - 受限的髓样转录因子是 完全了解髓样细胞基因表达。这些 实验对于更好地描述分子至关重要 从造血祖细胞中产生髓样细胞的事件 细胞。拟议的研究都与正常 造血（特别是髓样细胞）发育 造血肿瘤的分子发病机理。