STAT3 AND G-CSF MEDIATED MYELOID DIFFERENTIATION

STAT3 和 G-CSF 介导的骨髓分化

• 批准号: 6077888
• 负责人: ARUP CHAKRABORTY
• 金额: $ 0.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-10-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6077888
• 关键词: DNA binding protein; JAK kinase; acute myelogenous leukemia; antisense nucleic acid; biological signal transduction; cell differentiation; clone cells; colony stimulating factor; enzyme activity; enzyme inhibitors; gene expression; growth factor receptors; isozymes; mitogen activated protein kinase; myeloid stem cell; neoplastic cell; oligonucleotides; pathologic process; phenotype; transfection /expression vector

Despite newer treatment modalities, overall mortality from AML still exceeds 50 percent. Differentiation agents have shown promise but due to lack of efficacy and toxicity we are still looking for additional or better agents. In the initial studies, G-CSF could override the differentiation block in leukemic cell lines and in some fresh AML cells. However, most responsive AML cells proliferated without differentiation upon exposure to G-CSF. Based on our recent studies we postulate that in AML cells, Stat3alpha activation may interfere with the G-CSF-driven differentiation signal. In this proposal, we plan to determine 1) if Stat3 is required for G-CSF-driven myeloid differentiation, and 2) the effect of altered relative levels of Stat3 isoforms Stat3alpha and Stat3beta on G-CSF-driven myeloid differentiation. By meals of antisense inhibition of Stat3 and use of a dominant negative of Stat3, we shall confirm the role of Stat3 in myelopoiesis. Then by overexpressing Stat3alpha, we shall examine the role of relative Stat3 isoforms level in G-CSF-driven myelopoiesis. The long-term goal of this project is to apply information gained from these studies to the design of new differentiation-inducing agents for the treatment of AML. Such therapies might target Stat3alpha at the level of its activation or expression in AML cells.

尽管治疗方式更新，但AML的总体死亡率仍然 超过50％。 分化剂表现出希望，但应有 由于缺乏疗效和毒性，我们仍在寻找其他或 更好的代理。 在最初的研究中，G-CSF可以覆盖 白血病细胞系中的分化块和一些新鲜的AML 细胞。 但是，大多数响应迅速的AML细胞在没有的情况下增殖 暴露于G-CSF时的区分。 根据我们最近的研究 假设在AML细胞中，Stat3alpha激活可能会干扰 G-CSF驱动的分化信号。 在此提案中，我们计划 确定1）如果G-CSF驱动的髓样需要STAT3 分化和2）STAT3相对水平改变的影响 G-CSF驱动的髓样的同工型Stat3alpha和Stat3Beta 分化。通过对STAT3的反义抑制和使用 STAT3的主要负面负面，我们将确认STAT3在 骨髓。 然后，通过过表达Stat3alpha，我们将检查 相对STAT3同工型在G-CSF驱动的骨髓虫素中的作用。 这 该项目的长期目标是应用从这些信息中获得的信息 研究设计新的差异化剂的设计 AML的处理。 这种疗法可能针对水平的stat3alpha 其在AML细胞中的激活或表达。