DIFFERENTIATION OF GRANULOCYTES AND MACROPHAGES

本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，并定义这些分子的缺陷 导致髓系白血病形成的细胞。强调…… 该项目一直在通过分子对这些细胞进行外部调节。 调节器及其细胞受体，因为它们提供了干预 提高癌症患者造血恢复率的策略 治疗，纠正一些血液系统疾病的缺陷和 控制髓系白血病细胞的行为。之前在以下方面的进展 这笔赠款在一定程度上导致了目前至少两种药物的临床应用 造血分子调节剂(GM-CSF和G-CSF)和场景现在是 为使用下一代分子调节器而设计的集 基于对相互作用的完全分子理解 在这些调节因子和它们的受体亚基之间。现在 建议使用克隆的定点突变策略 调节剂及其受体亚单位执行详细的生化 并对这些突变体进行生物学分析。这些结果将允许 特定结合中所涉及的结构元素的测定 受体亚单位的调节聚集和激活 递送增殖和分化细胞的受体 信号。重点将放在两个特定的监管系统上 粒细胞-巨噬细胞集落刺激因子、GM-CSF与白血病 抑制因子，LIF)，提供了不同的视角 可以预期的细胞反应。抗肿瘤的单抗 受体亚基也会同时产生，以定义重要的 受体中的结构元素，并通过 免疫沉淀细胞中的信号转导元件是什么 与激活的受体复合体相关。自然发生的和 人工可溶受体也将作为潜在的 造血生长因子全身性效应的调节机制 特别强调一种血清LIF结合蛋白，似乎 防止这种高度多效性细胞因子的系统性传播。 终于来了。体内模型将被开发来测试多个 造血调节剂与多受体刺激对行为的影响 作为未来临床试验的前奏。结果是 这项工作有望成为一种更合理的治疗性设计 可以针对外在行为的特定方面的策略 造血细胞的调节器。

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.