DIFFERENTIATION OF GRANULOCYTES AND MACROPHAGES

调节生产和生产的群体刺激因子(CSF) 粒细胞和巨噬细胞的活性目前被用于 对生产或生产中存在缺陷的患者进行广泛的临床试验 这些细胞的功能或免疫功能受损或 提高细胞毒治疗和/或治疗后的造血恢复率 癌症患者的骨髓移植。的长期目标 这个项目是为了详细地了解分子的结构 CSF及其细胞受体，CSF递送的机制 它们对细胞的信号、对CSF的产生和作用的调节 在控制粒细胞-巨噬细胞群和分子缺陷方面 这是恶性髓系白血病细胞行为的基础。这个 目前的应用是从细胞中分离出可溶性的CSF受体 形成并重建在完整细胞中看到的结合参数。而当 这些研究将在纯化的受体上进行，这些受体从 细胞，也将进行分子克隆脑脊液受体的尝试 用放射性CSF筛选COS细胞表达文库 放射自显影。如果这是成功的，它将提供手段 详细分析脑脊液受体的结构，并通过受体确定 转染学，信号转导所需的组件。它 并建议从整体上分析髓系白血病的发展。 与人类情况惊人相似的动物模型和 以确定他们对CSF的反应模式以及基因 改变，这可能涉及脑脊液基因，导致他们的恶性 行为。最后，将研究脑脊液的表达和调节。 正常细胞和慢性GM-CSF暴露模型(GM-CSF中 转基因小鼠)，这与可能的病理效应有关 在接受脑脊液治疗的患者中被看到。

The colony stimulating factors (CSFs) which regulate the production and activity of granulocytes and macrophages are currently being used in extensive clinical trials on patients with defects in the production or function of these cells or in patients that are immunocompromised or to enhance the rate of hemopoietic recovery after cytotoxic therapies and/or bone marrow transplantation in patients with cancer. The long-term aims of this project are to understand in molecular detail the structures of the CSFs and their cellular receptors, the mechanisms by which CSFs deliver their signals to cells, the regulation of the production and action of CSFs in controlling granulocyte-macrophage populations and the molecular defects that underlie the behavior of malignant myeloid leukemic cells. The present application is to isolate CSF receptors from cells in a soluble form and to reconstruct the binding parameters seen in intact cells. While these studies will be carried out on purified receptors extracted from cells, major attempts will also be made to molecularly clone CSF receptors by screening expression libraries in COS cells with radioactive CSFs and autoradiography. If this is successful it will provide the means to analyze CSF receptor structures in detail and to determine, by receptor transfection studies, the components required for signal transduction. It is also proposed to analyze the development of myeloid leukemia in whole animal models that bear a striking resemblance to the human situation and to determine their responsiveness patterns to CSFs as well as the genetic alterations, that may involve CSF genes, leading to their malignant behavior. Finally, CSF expression and modulation will be examined in normal cells as well as a model of chronic GM-CSF exposure (in GM-CSF transgenic mice) that has relevance to the pathological effects that might be seen with CSF treatment in patients.