GROWTH REGULATION IN NORMAL AND TRANSFORMED PHAGOCYTES

正常和转化吞噬细胞的生长调节

• 批准号: 3191083
• 负责人: BEN D CHEN
• 金额: $ 12.77万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3191083
• 关键词: biological signal transduction; cell differentiation; cell growth regulation; cell transformation; colony stimulating factor; cytokine receptors; laboratory mouse; leukocyte activation /transformation; monocyte; neoplastic cell culture for noncancer research; phosphorylation; protooncogene; receptor coupling; tissue /cell culture

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.

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 刺激因素（CSF）。 在小鼠中，大多数巨噬细胞前体细胞 同时显示多种类型的 CSF 受体并对 CSF 做出反应 单独或组合。 尽管它们看起来冗余且 生物效应重叠，CSF 以分层和协调的方式发挥作用 的方式来控制巨噬细胞的增殖和分化。 受体结合测定表明，尽管 CSF 不共享每个 其他受体位点，它们可以诱导快速短暂的下调 其他 CSF 受体。 然而，虽然 J774 单核细胞样肿瘤细胞 显示多个 CSF 受体系统，但它们不显示受体 在正常对应物中看到的反式调制。 我们的工作假设 各种 CSF 受体通过信号网络连接 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 根据这个假设，我们将首先研究相关的生化变化 受体反式调节及其在正常情况下的生物学意义 巨噬细胞及其白血病对应物 J774 细胞。 接下来，我们将 研究受体-受体相互作用的生化基础 并确定导致白血病中受体解偶联的原因 细胞。 最后，我们将研究生物反应是否与 受体反式调节也在基因水平上受到调节。 该提案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 连接增殖和分化过程的相互作用 在造血细胞中。