CYTOKINE SIGNALING IN MYELOID LEUKEMIAS

粒细胞白血病中的细胞因子信号转导

• 批准号: 2091960
• 负责人: MICHAEL B LILLY
• 金额: $ 9.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091960
• 关键词: antisense nucleic acid; apoptosis; biological signal transduction; colony stimulating factor; cytokine; gene expression; hematopoietic growth factor; myelogenous leukemia; neoplasm /cancer immunology; phenotype; plasmids; polymerase chain reaction; recombinant proteins; tissue /cell culture; transfection; western blottings

DESCRIPTION: (Adapted from applicant's abstract)This application seeks to characterize critical steps in the proliferative signalling pathways activated by GM-CSF in related cytokines in primitive myeloid cells. At least some cases of myeloid leukemia likely result from over activity of such signal pathways. Identification of critical or unique steps in such cascades may allow development of pharmacologic interventions to specifically disrupt these pathways. The specific hypothesis of this application is that expression of the pim-1 gene project, a 33 kd serine/threonine kinase, is necessary for effective proliferative signalling through GM-CSF and related receptors. The applicant further hypothesizes that pim-1 expression serves as a specific indicator of activation of such pathways. The hypothesis will be investigated by constructing cell systems which allow for the over expression or blockade of pim-1 activity. Factor-dependent myeloid cell lines will be transfected with plasmid constructs or retroviral constructs to allow autonomous expression of the pim-1 gene product.These lines will then be examined for factor- independent growth, impaired differentiation, inhibition of apoptosis and homotypic aggregation. Similar cell lines will be created utilizing plasmids containing antisense pim-1 constructs to inhibit activity of the endogenous pim-1 gene. These cells will be studied for the responsiveness to GM-CSF and related cytokines and their propensity to differentiation.

描述：（改编自申请人的摘要）此申请寻求 在增殖信号通路中表征关键步骤 在原始髓样细胞中的相关细胞因子中被GM-CSF激活。在 至少有些髓样白血病可能是由于过度活动而引起的 这种信号途径。 确定关键或独特步骤 这种级联可能允许开发药理干预措施 特别破坏这些途径。 特定假设 应用是PIM-1基因项目的表达，一个33 kD 丝氨酸/苏氨酸激酶是有效增殖所必需的 通过GM-CSF和相关受体的信号传导。 申请人进一步 假设PIM-1表达是 这种途径的激活。 该假设将通过 构建允许过度表达或封锁的单元系统 PIM-1活性。 因子依赖性髓样细胞系将是 用质粒构建或逆转录病毒构建体转染 然后，PIM-1基因产物的自主表达。 检查因素独立生长，分化受损， 抑制细胞凋亡和同型聚集。 类似的细胞系 将使用含有反义PIM-1构建体的质粒创建 抑制内源性PIM-1基因的活性。 这些细胞将是 研究了对GM-CSF及其相关细胞因子及其的反应性 分化的倾向。