ROLE OF HCK IN MYELOID DIFFERENTIATION AND ACTIVATION

HCK 在骨髓分化和激活中的作用

• 批准号: 3464673
• 负责人: BOYCE K ENGLISH
• 金额: $ 9.3万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3464673
• 关键词: cell differentiation; clone cells; colony stimulating factor; enzyme activity; enzyme inhibitors; gene expression; gene induction /repression; genetic regulation; hematopoietic stem cells; human subject; interleukin 1; interleukin 6; leukocyte activation /transformation; lipopolysaccharides; macrophage; monocyte; myeloid stem cell; phosphorylation; protein biosynthesis; protein structure function; protein tyrosine kinase; reporter genes; transfection; tumor necrosis factor alpha

The tyrosine phosphorylation of specific protein substrates is an integral component of signal transduction pathways that mediate cellular differentiation and activation pathways. The pattern of expression of certain members of the src family of protein tyrosine kinases (and, in some cases, their association with surface receptors) suggested that these kinases are involved in these signal transduction pathways in hematopoietic cells. This hypothesis has been strengthened by recent functional studies that support the role of two src-related kinases, lck and fyn, in T cell activation. The hck gene is expressed in myeloid cells of both monocyte/macrophage and granulocyte lineages and is most highly expressed in mature cells of both lineages. The long term goal of this proposed research is to define the role of the hck protein in macrophage activation and myeloid differentiation. The primary strategy of this work is to manipulate the expression of hck or "activated" or "dead" mutants of the kinase in myeloid cells in order to explore the role of hck in activation and differentiation pathways. Preliminary data from this laboratory suggest that hck expression is not essential for granulocytic differentiation but do not exclude an important role of the kinase in mature granulocyte function. Preliminary studies in the murine macrophage line, Bac 1.2F5, show a strong correlation between hck expression and the activation of these cells to produce cytokines such as tumor necrosis factor (TNF). We hypothesize that hck expression is necessary though not sufficient for normal monocyte/macrophage differentiation and that hck plays an important role in the activation pathways of mature macrophages that lead to cytokine gene expression. Thus, the specific aims of this proposal are (1) To determine the role of hck in macrophage activation and the regulation of cytokine gene expression; (2) To determine the function of hck in monocyte/macrophage differentiation; and (3) To study the regulation of hck production, tyrosine kinase activity and subcellular localization in myeloid cells. These studies should significantly improve our understanding of the role of tyrosine kinases as critical components of the signal transduction pathways in hematopoietic cells.

特定蛋白质底物的酪氨酸磷酸化是一个不可或缺的过程， 信号转导通路的组成部分，介导细胞 分化和激活途径。 表达模式 蛋白酪氨酸激酶的src家族的某些成员（并且，在一些实施方案中， 例，它们与表面受体的联系）表明，这些 激酶参与造血细胞中的这些信号转导途径， 细胞 这一假设已被最近的功能研究所加强 支持两种src相关激酶lck和fyn在T细胞中的作用， activation. hck基因在两种骨髓细胞中都有表达， 单核细胞/巨噬细胞和粒细胞谱系， 在两个谱系的成熟细胞中。 提出的长期目标 研究是确定hck蛋白在巨噬细胞活化中的作用 和骨髓分化。 这项工作的主要战略是 操纵hck的表达或hck的“激活的”或“死亡的”突变体， 目的探讨hck在髓系细胞活化中的作用。 和分化途径。 这个实验室的初步数据 提示hck表达对于粒细胞 分化，但不排除激酶的重要作用， 成熟粒细胞功能。 小鼠巨噬细胞中的初步研究 Bac 1.2F5细胞系hck表达与细胞凋亡之间有很强的相关性。 激活这些细胞产生细胞因子，如肿瘤坏死 因子（TNF）。 我们假设hck的表达是必要的， 足以用于正常单核细胞/巨噬细胞分化和HCK 在成熟巨噬细胞的活化途径中起重要作用 导致细胞因子基因表达。 因此，这一具体目标 建议：（1）确定hck在巨噬细胞活化中的作用， 细胞因子基因表达的调控;（2）确定细胞因子基因表达的功能 hck在单核细胞/巨噬细胞分化中的作用;和（3）研究hck在单核细胞/巨噬细胞分化中的作用 调节hck的产生，酪氨酸激酶活性和亚细胞 在骨髓细胞中的定位。 这些研究将大大改善 我们对酪氨酸激酶的作用的理解， 造血细胞中的信号转导途径。