CYTOKINE REGULATION OF EOSINOPHIL GENES

已知嗜酸性粒细胞参与了几种 疾病。这些疾病包括过敏性和寄生虫病。两者都有 骨髓中的嗜酸性粒细胞分化和成熟也是如此 作为有丝分裂后的功能激活和延长的生存 组织中的嗜酸性粒细胞是对细胞因子的反应。几个 研究表明，只有IL-5是嗜酸性粒细胞所特有的。先前的研究 已经证明IL-5通过一种异二聚体发挥作用 细胞表面受体具有共享的β亚基和独特的 阿尔法亚单位。这两个组件都是最佳信号所必需的 转导。目前对其分子机制一无所知 嗜酸性粒细胞分化诱导过程中的转录调控 或IL-5RA基因的谱系特异性表达 多潜能的髓系祖细胞或发育中的嗜酸性粒细胞。这个 其具体目的是研究其分子机制。 嗜酸性粒细胞中IL-5RA基因的转录调控 发展。提出了三个具体目标：1)什么是 嗜酸性粒细胞的转录和转录后机制 IL-5R基因在小鼠胚胎发育过程中的特异性表达 嗜酸性粒细胞系的多潜能髓系祖细胞。2)什么 IL-5RA启动子中的转录调控元件 负责嗜酸性粒细胞特异性表达和上调 嗜酸性粒细胞活性细胞因子的表达？3)什么是 构成或细胞因子诱导的转录因子反应 利用这些调控元件调控IL-5RA的表达 吉恩？申请者将克隆并鉴定反式作用因子 (从EOS开始！最近发现的核因子)，是 显示对嗜酸性粒细胞特异性IL-5RA基因的表达至关重要 并分析了选择性剪接产生的调控机制 可溶型与跨膜型受体。

Eosinophils are known to be involved in the pathogenesis of several diseases. These include allergic and parasitic diseases. Both eosinophil differentiation and maturation in the bone marrow, as well as the post-mitotic functional activation and prolonged survival of eosinophils in tissues occurs in response to cytokines. Several studies indicate only IL-5 is specific for eosinophils. Prior studies have demonstrated that IL-5 exerts its effect through a heterodimeric cell surface receptor which has a shared beta subunit and a unique alpha subunit. Both components are required for optimal signal transduction. Nothing is known of the molecular mechanisms for transcriptional regulation in the induction of eosinophil differentiation or the lineage-specific expression of the IL-5Ra gene by multipotential myeloid progenitors or the developing eosinophil. The specific aims are to investigate the molecular mechanisms for transcriptional regulation of the IL-5Ra gene in eosinophil development. Three specific aims are proposed: 1) What are the transcriptional and post-transcriptional mechanisms for eosinophil- specific expression of the IL-5R gene during the commitment of multipotential myeloid progenitors to the eosinophil lineage. 2) What are the transcriptional regulatory elements in the IL-5Ra promotor responsible for eosinophil -specific expression and up-regulation of expression by eosinophil-active cytokines? 3) What are the constitutive or cytokine -induced transcriptional factors which react with these control elements to regulate expression of the IL-5Ra gene? The applicant will clone and characterize trans-acting factors (starting with the EOS! Nuclear factor identified recently) that are shown to be critical for eosinophil -specific IL-5Ra gene expression and analyze the mechanisms regulating alternative splicing to produce soluble versus transmembrane forms of the receptor.