Role of Eotaxin-3/CCL26 in Allergic Asthma

描述(由申请人提供)：表达Th2细胞因子的T淋巴细胞在过敏性呼吸道疾病的发展中起关键作用，但从大量研究中可以清楚地看出，嗜酸性粒细胞也参与了哮喘的发病机制。我们实验室最近利用儿童哮喘的非人类灵长类动物模型，研究了eoaxin/CCL11、eoaxin-2/CCL24和eoaxin-3/CCL26作为趋化因子在变应原诱导的嗜酸性粒细胞募集中的作用。我们已经证明，变应原诱导的嗜酸性粒细胞在幼猴肺中的募集与气道上皮内嗜酸粒细胞趋化因子-3/CCL26表达的升高显著相关。基于这些发现，我们推测Eoaxin-3/CCL26的表达在吸入过敏原后嗜酸性粒细胞进入呼吸道的过程中起着重要作用。为了解决我们的假设，这项R03试验方案的主要目标是开发一种小鼠模型，以评估eoaxin-3/CCL26在过敏性呼吸道疾病发展中的功能作用。这项应用的第一个具体目标将集中在细胞和分子方法上，以表征人嗜酸性粒细胞趋化蛋白-3/CCL26的小鼠同源物。第二个特定的目的是随后产生一个eoaxin-3/CCL26靶向缺失突变小鼠，在卵蛋白致敏后，它将在过敏性哮喘模型的背景下定义这种嗜酸性趋化因子的病理作用。在这个项目完成后，我们将确定一种新的嗜酸性趋化因子的假定病理生理学作用；这将有助于我们全面了解肺内复杂的趋化因子网络如何在过敏性哮喘中调节嗜酸性粒细胞的运输。识别促进过敏性哮喘的趋化因子是未来以呼吸道内特定分子为靶点的治疗方法的重要一步。

DESCRIPTION (provided by applicant): T lymphocytes that express a Th2 cytokine profile play a pivotal role in the development of allergic airways disease, yet it is clear from numerous studies that eosinophils also contribute to the pathogenesis of asthma. Our laboratory has recently investigated eotaxin/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 as chemokine mediators of allergen-induced eosinophil recruitment using a non-human primate model 'of childhood asthma. We have demonstrated that allergen-induced eosinophil recruitment into the infant monkey lung significantly correlates with elevated expression of eotaxin-3/CCL26 within airway epithelium. Based on these findings, we hypothesize that eotaxin-3/CCL26 expression by airway epithelium plays an important role in the trafficking of eosinophils into airways following aeroallergen exposure. To address our hypothesis, the primary objective of this R03 pilot proposal is to develop a mouse model to assess the functional role of eotaxin-3/CCL26 in the development of allergic airways disease. The first specific aim of this application will focus on cellular and molecular approaches to characterize a mouse homologue for human eotaxin-3/CCL26. The second specific aim will subsequently generate an eotaxin-3/CCL26 targeted deletion mutant mouse which, following sensitization with ovalbumin, will define the pathologic role for this eosinophilic chemokine within the context of an allergic asthma model. At the completion of this project, we will have defined a putative pathophysiologic role for a novel eosinophilic chemokine; this will contribute to our overall understanding of how the complex chemokine network within the lung regulates trafficking of eosinophils in allergic asthma. The identification of chemokines that promote allergic asthma is an important step in the future development of therapeutics to target specific molecules within the airways.