REGULATION OF MYELOPOIESIS: SUPPRESSOR FACTOR SYNERGISM

骨髓生成的调节：抑制因子的协同作用

• 批准号: 3174322
• 负责人: HAL E. BROXMEYER
• 金额: $ 23万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3174322
• 关键词: Friend virus; cell growth regulation; cell sorting; clone cells; colony stimulating factor; erythropoietin; ferritin; gene expression; growth inhibitors; hematopoietic growth factor; hematopoietic stem cells; human subject; immunohematology; interferons; interleukin 3; laboratory mouse; leukopoiesis; leukopoietic factor; monoclonal antibody; myelogenous leukemia; myeloproliferative neoplasm; neoplasm /cancer immunology; neoplasm /cancer remission /regression; neoplastic growth; oncogenes; prostaglandin E; radioimmunoassay; receptor; tumor necrosis factor alpha

The control of proliferation of hematopoietic stem and progenitor cells in vivo is most likely the end result of the production and action of growth-stimulating and growth-suppressing molecules. We have defined and characterized the influence of purified natural and recombinant molecules such as acidic isoferritins, the interferons gamma, alpha and beta, the E type prostaglandins, and tumor necrosis factor on normal and abnormal hematopoiesis. Of much interest to us, and potentially of great importance and relevance to an understanding of the physiological regulation of hematopoietic cell proliferation in vivo and of abnormalities in this regulation during leukemia and related blood disorders is the recent findings by us and others that certain molecules can synergise with each other in vitro so that the effects noted are much greater than additive. We propose to investigate the phenomenon of synergism between molecules in vitro and in vivo. Our aims are to evaluate further and more precisely the actions and interactions alone and in combination of well-characterized and purified natural or recombinant acidic isoferritins, interferons-gamma and -alpha, prostaglandin E1 or E2 and tumor necrosis factor on the growth in vitro of fresh primary normal human and murine myeloid cells, on cells from patients with leukemia and related disorders, and on established human myeloid leukemia cell lines in vitro. Our goal is to study these molecule-cell interactions using pure molecules and purified populations of target cells, isolated by biophysical and immunological procedures, in the presence and absence of serum. Studies in vitro will include an analysis of the activity of these molecules using colony forming cell assays (CFU-GM, BFU-E, CFU-GEMM, S-cells), the receptor-binding capacity of these molecules, and effects of these molecules on the expression of proto-oncogenes. We also propose to evaluate the separate and combined actions of these molecules in vivo in mice undergoing rebound myelopoiesis, in untreated mice, and in mice infected with the Friend Viruis Complex. We believe that the studies proposed will increase our understanding of the relevance of these molecules and the concept of synergism as it applies to normal and abnormal regulation.

造血干/祖细胞增殖的调控 体内最有可能是生产和行动的最终结果， 生长刺激和生长抑制分子。 我们定义了 表征了纯化的天然和重组分子的影响， 如酸性异铁蛋白，干扰素γ、α和β，E 型前列腺素和肿瘤坏死因子对正常和异常 造血 我们很感兴趣，而且可能非常重要 和相关的生理调节的理解， 体内造血细胞增殖和这种异常 白血病和相关血液疾病的调节是最近的 我们和其他人的发现，某些分子可以协同每一个 其他的在体外，使得所注意到的效果比加和的效果大得多。 我们建议研究分子间的协同作用现象， 体外和体内。 我们的目标是进一步和更准确地评估 行动和相互作用单独和结合良好的特点， 纯化的天然或重组酸性异铁蛋白、干扰素-γ和 - α，前列腺素E1或E2和肿瘤坏死因子对生长的影响， 新鲜的原代正常人和鼠骨髓细胞的体外培养， 白血病和相关疾病的患者，以及已建立的人类 体外髓系白血病细胞系。 我们的目标是研究这些 分子-细胞相互作用，使用纯分子和纯化的 通过生物物理学和免疫学方法分离的靶细胞， 有无血清。 体外研究将包括分析 使用集落形成细胞测定这些分子的活性 （CFU-GM、BFU-E、CFU-GEMM、S细胞），这些细胞的受体结合能力 分子，以及这些分子对 原癌基因 我们还建议评估单独和合并的 这些分子在经历反跳性骨髓生成的小鼠体内的作用， 在未处理的小鼠中，以及在用Friend病毒复合体感染的小鼠中。 我们 我相信，这些研究建议将增加我们对 这些分子的相关性和协同作用的概念，因为它适用于 正常和异常调节。