IL 3, IL 5, AND GM-CSF SIGNALING AND ASTHMA

描述（改编自申请人的摘要）： 包括IL-3、IL-5和GM-CSF在内的配体参与了 哮喘的发病机制。 IL-5和GM-CSF均以升高的水平表达。 肺组织和分泌物中的水平 因为哮喘 这些细胞因子已被证明在 嗜酸性粒细胞、肥大细胞和一些 额外的促炎细胞。 进一步用IL-5治疗 特异性抗体已被证明可以阻断豚鼠的哮喘 模型 然而，这些细胞因子介导这些的机制是不确定的。 效果不佳。 最近，IL-3家族 被证明可以激活两种不同但相关的信号通路 这取决于靶细胞的分化状态。 该途径 在未成熟的髓样细胞中激活的信号转导因子 （STF-IL3a），其在生物化学上和功能上不同于 信号转导因子（STF-IL3b）在成熟骨髓细胞中活化。 这可能提供了第一个机械解释， 细胞因子可以是未成熟细胞中的必需生长因子， 具有重要但明显的促炎作用， 细胞（嗜酸性粒细胞和肥大细胞）。 编码该成分的基因 最近已克隆并发现STF-IL 3a的蛋白质（p77和p80 是Stat 5的同种型，这是一种首次基于以下能力描述的因子： 介导催乳素刺激的酪蛋白基因激活。 的 STF-IL-3b的组分具有不同的分子量（p94和p96）， 而且似乎是Stat5的同种型。 作者假设 这四种蛋白质是两种不同的类Stat 5蛋白的产物， 基因. 这些蛋白质的不同形式的产生可能是 在未成熟与成熟细胞中调节。 具体目标是 建议是：1。描述四个Stat 5的不同作用 在介导IL-3配体家族的信号中的同种型。 2. 识别两种信号传导中的其他配体特异性组分 由IL-3配体家族激活的级联反应。 3.针对 Stat 5亚型与IL 3 β受体之间的特异性相互作用 链中断。

DESCRIPTION (Adapted from the applicant's abstract): The IL-3 family of ligands, which include IL-3, IL-5 and GM-CSF, have been implicated in the pathogenesis of asthma. Both IL-5 and GM-CSF are expressed at elevated levels in the pulmonary tissues and secretions of patients suffering from asthma. These cytokines have been shown to play a crucial role in the growth and activation of eosinophils, mast cells, and several additional pro-inflammatory cells. Furthermore treatment with IL-5 specific antibodies has been shown to block asthma in the guinea pig model. However, the mechanism by which these cytokines mediate these effects has been poorly characterized. Recently, the IL-3 family has been shown to activate two distinct, but related signaling pathways depending on the differentiation state of the target cell. The pathway activated in immature myeloid cells employs a signal transducing factor (STF-IL3a) that is biochemically and functionally distinct from the signal transducing factor (STF-IL3b) activated in mature myeloid cells. This may provide the first mechanistic explanation of how the same cytokine can be both an essential growth factor in immature cells and have an important but distinct pro-inflammatory effect on more mature cells (eosinophils and mast cells). The genes encoding the component proteins (p77 and p80) of STF-IL3a have recently been cloned and found to be isoforms of Stat 5, a factor first described based on the ability to mediate prolactin- stimulated activation of casein genes. The components of STF-IL-3b have distinct molecular weights (p94 and p96), but also appear to be isoforms of Stat 5. The authors have hypothesized that these four proteins are the products of two distinct Stat 5-like genes. The generation of different forms of these proteins may be regulated in immature vs. mature cells. The specific aims of this proposal are to: 1. Characterize the differential role of four Stat 5 isoforms in mediating signals for the IL-3 family of ligands. 2. Identify additional ligand specific components in the two signaling cascades activated by the IL-3 family of ligands. 3. Target the specific interactions between Stat 5 isoforms and the IL3beta receptor chain for interruption.