GROWTH REGULATION IN NORMAL AND TRANSFORMED PHAGOCYTES

单核吞噬细胞的增殖和分化是 由一组称为集落的造血生长因子调节， 刺激因子（CSF）。 在小鼠中，大多数巨噬细胞前体细胞 同时显示几种类型的CSF受体，并对CSF作出反应 单独或组合使用。 尽管他们看起来冗余， 生物效应重叠，CSF以分层和协调的方式发挥作用， 控制巨噬细胞增殖和分化的方式。 受体结合试验表明，虽然CSF不共享每个 其他的受体位点，它们可以诱导快速的瞬时下调 其他CSF受体。 然而，尽管J774单核细胞样肿瘤细胞 显示多种CSF受体系统，它们不显示受体 在它们的正常对应物中看到的反调制。 我们的工作假设 不同的CSF受体通过信号网络联系在一起， 造血细胞的增殖和分化过程 细胞是耦合的。 据认为，CSF之间的解偶联 造血细胞中的受体可能导致分化停滞， 白血病细胞不受控制的增殖特征。 验证 我们将首先研究与此相关的生化变化， 受体反式调节及其生物学意义 巨噬细胞和它们的白血病对应物J774细胞。 接下来我们就 研究负责受体-受体相互作用的生物化学基础 并确定导致白血病患者受体解偶联的原因， 细胞 最后，我们将研究是否有相关的生物反应， 受体反式调节也在遗传水平上受到调节。 本建议的总体目标是更深入地了解 受体-受体相互作用的生物学意义及其作用 在连接增殖和分化过程中的相互作用 在造血细胞中。

The proliferation and differentiation of mononuclear phagocytes are regulated by a group of hemopoietic growth factors known as colony- stimulating factors (CSFs). In mouse, most macrophage precursor cells display several types of CSF receptors simultaneously and respond to CSFs either alone or in combination. Despite their seeming redundancy and overlap in biologic effects, CSFs act in a hierarchical and coordinated manner toward the control of macrophage proliferation and differentiation. Receptor binding assay indicates that although CSFs do not share each other's receptor sites, they can induce a rapid transient down-regulation of other CSF receptors. However, although J774 monocyte-like tumor cells display multiple CSF receptor systems, they do not exhibit the receptor trans-modulation seen in their normal counterparts. Our working hypothesis is that various CSF receptors are linked through a signaling network by which the processes of proliferation and differentiation in hemopoietic cells are coupled. It is thought that the un-coupling between CSF receptors in hemopoietic cells may lead to the arrested differentiation and uncontrolled proliferation characteristic of leukemic cells. To verify that hypothesis, we will first study the biochemical changes associated with receptor trans-modulation and their biologic significance in normal macrophages and their leukemic counterparts, J774 cells. Next, we will study the biochemical basis responsible for receptor-receptor interaction and determine the causes leading to receptor-uncoupling seen in leukemic cells. Finally, we will study whether the biologic responses associated with receptor trans-modulation are regulated at genetic levels as well. The overall objective of this proposal is to gain more insight into the biologic significance of receptor-receptor interaction and the role of this interaction in linking the processes of proliferation and differentiation in hemopoietic cells.