Role of Eotaxin-3/CCL26 in Allergic Asthma

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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.