DIFFERENTIATION OF GRANULOCYTES AND MACROPHAGES

粒细胞和巨噬细胞的分化

• 批准号: 3165856
• 负责人: DONALD METCALF
• 金额: $ 9.75万
• 依托单位: WALTER AND ELIZA HALL INST MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-03-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165856
• 关键词: binding proteins; cell differentiation; cell growth regulation; cellular oncology; colony stimulating factor; cytokine receptors; disease /disorder model; genetically modified animals; granulocyte; growth factor receptors; hematopoiesis; hematopoietic growth factor; hybrid cells; immunoprecipitation; immunoregulation; interleukin 6; laboratory mouse; macrophage; migration inhibition factor; model design /development; molecular oncology; monoclonal antibody; myelogenous leukemia; protein reconstitution; protein structure function; receptor binding; site directed mutagenesis

The long term aims of this project are to understand the control of the production and function of granulocytes and macrophages at both the cellular and molecular level and to define the molecular defects in those cells that lead to the formation of myeloid leukemia. The emphasis of the project has been on external regulation of these cells by molecular regulators and their cellular receptors since these provide intervention strategies for increasing the rate of hemopoietic recovery in cancer therapies, correcting defects in some hemopoietic diseases and controlling the behavior of myeloid leukemic cells. Previous progress on this grant has led in part to the current clinical use of at least two hemopoietic molecular regulators (GM-CSF and G-CSF) and the scene is now set for the use of the next generation of molecular regulators designed on the basis of a full molecular understanding of the interactions between these regulators and their receptor subunits. The present proposal is to use site-directed mutational strategies of cloned regulators and their receptor subunits to perform a detailed biochemical and biological analysis of these mutants. These results will allow a determination of the structural elements involved in specific binding of the regulator aggregation of receptor subunits and activation of the receptor for delivering proliferative and differentiative cellular signals. Emphasis will be placed on two particular regulatory systems (granulocyte-macrophage colony-stimulating factor, GM-CSF and leukemia inhibitory factor, LIF) that offer different perspectives on the types of cellular responses that can be expected. Monoclonal antibodies to receptor subunits will also be generated both to define important structural elements in the receptors and to determine by immunoprecipitation what signal transducing elements in cells become associated with activated receptor complexes. Naturally occurring and artificial soluble receptors will also be explored as potential regulators of the systemic effects of hemopoietic growth factors with particular emphasis on a serum LIF-binding protein that appears to prevent the systemic spread of this highly pleiotropic cytokine. Finally. in vivo models will be developed to test the effects of multiple hemopoietic regulators and multiple receptor stimulation on the behavior of hemopoietic cells as a prelude to future clinical trials. The outcome of this work is expected to be a more rational design of therapeutic strategies that can target specific aspects of the actions of extrinsic regulators on hemopoietic cells.

该项目的长期目标是了解 粒细胞和巨噬细胞的产生和功能 细胞和分子水平并定义这些细胞和分子水平的分子缺陷 导致髓性白血病形成的细胞。 强调的是 该项目一直致力于通过分子对这些细胞进行外部调节 调节剂及其细胞受体，因为它们提供干预 提高癌症造血恢复率的策略 疗法，纠正某些造血系统疾病的缺陷和 控制骨髓白血病细胞的行为。 先前的进展 这笔赠款部分导致了目前至少两种的临床使用 造血分子调节剂（GM-CSF和G-CSF）现在的情况 一套专为使用下一代分子调节剂而设计的 基于对相互作用的全面分子理解 这些调节剂及其受体亚基之间。 现在的 建议使用克隆的定点突变策略 调节器及其受体亚基执行详细的生化 以及这些突变体的生物学分析。 这些结果将允许 确定参与特异性结合的结构元件 受体亚基的调节聚集和激活 传递增殖和分化细胞的受体 信号。 重点将放在两个特定的监管体系上 （粒细胞-巨噬细胞集落刺激因子、GM-CSF 和白血病 抑制因子（LIF），提供了对不同类型的不同观点 可以预期的细胞反应。 单克隆抗体 受体亚基也将被生成来定义重要的 受体中的结构元件并确定 免疫沉淀细胞中的信号转导元件变成什么 与激活的受体复合物有关。 自然发生和 人工可溶性受体也将作为潜在的探索 造血生长因子系统效应的调节因子 特别强调血清 LIF 结合蛋白 防止这种高度多效性细胞因子的全身扩散。 最后。将开发体内模型来测试多种药物的效果 造血调节剂和多重受体刺激对行为的影响 造血细胞作为未来临床试验的前奏。 结果 这项工作的目的是希望能有一个更加合理的治疗设计 可以针对外在行为的特定方面的策略 造血细胞的调节因子。