Role of Eotaxin-3/CCL26 in Allergic Asthma

描述（由申请人提供）：表达Th 2细胞因子谱的T淋巴细胞在过敏性气道疾病的发展中起关键作用，但许多研究表明嗜酸性粒细胞也有助于哮喘的发病机制。我们的实验室最近研究了eotaxin/CCL 11，eotaxin-2/CCL 24，和eotaxin-3/CCL 26作为趋化因子介导的过敏原诱导的嗜酸性粒细胞募集使用非人灵长类动物模型的儿童哮喘。我们已经证明，过敏原诱导的嗜酸性粒细胞募集到幼猴肺中与气道上皮内eotaxin-3/CCL 26表达升高显著相关。基于这些发现，我们推测气道上皮细胞表达的嗜酸性粒细胞趋化因子-3/CCL26在吸入过敏原后嗜酸性粒细胞进入气道的运输中起重要作用。为了解决我们的假设，该R 03试点提案的主要目的是开发小鼠模型以评估嗜酸性粒细胞趋化因子-3/CCL26在过敏性气道疾病发展中的功能作用。本申请的第一个具体目的将集中于表征人嗜酸性粒细胞趋化因子-3/CCL26的小鼠同源物的细胞和分子方法。第二个具体目标将随后产生嗜酸性粒细胞趋化因子-3/CCL26靶向缺失突变小鼠，其在用卵清蛋白致敏后，将确定该嗜酸性粒细胞趋化因子在过敏性哮喘模型中的病理作用。在这个项目完成后，我们将确定一个假定的病理生理作用的一种新的嗜酸性粒细胞趋化因子，这将有助于我们全面了解复杂的趋化因子网络如何在肺调节嗜酸性粒细胞在过敏性哮喘的运输。促进过敏性哮喘的趋化因子的鉴定是未来开发针对气道内特定分子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.