Disability and death caused by asthma has increased in developed nations during the past 50 years. One cytokine, IL-13, has been strongly implicated in asthma pathogenesis by both animal and human studies. Consequently, IL-13 has become an important target for developing novel asthma therapies. Better understanding of the production, regulation, and effector mechanisms of IL- 13 is required to optimize any IL-13 related therapy. This Program Project responds to this requirement by investigating the importance of IL-13 in mouse models of asthma in an integrated fashion. Project I will use gene-targeted mice to evaluate the connection between IL-13 suppression of NKCC1, a Na+/K+/2CI- co-transporter expressed by lung epithelial cells, and IL-13 induction of airway hyperresponsiveness (AHR) and mucus overproduction. Project 2 will evaluate the unique characteristics of IL-13 that make it more important than the similar cytokine, IL-4, in asthma. Experiments in this component will feature mice that express the IL-4Ralpha component of the IL- 13 receptor on a single cell type or on all cells but a single cell type, as well as studies of a small set of genes that appear to be induced exclusively by IL-13. Project 3 will evaluate how interactions among IL-13, chemokines, and eosinophils act synergistically to promote pulmonary inflammation and will evaluate how one chemokine, Mig, can inhibit the effects of IL-13. Project 4 will evaluate how an IL-13-binding protein, IL-13R-alpha2, has both positive and negative effects on IL-13-induced AHR and airway inflammation. All scientific components will interact with each other by generating and sharing animals and reagents and by creating a conceptual framework that allows for optimal interpretation of all acquired data. Administrative, """"""""Pathology and Gene Expression,"""""""" and """"""""Breeding and Genotyping"""""""" cores will promote collaborations between the investigators and improve the efficiency with which the proposed studies are performed. Integration of the studies performed should provide a comprehensive understanding of the unique role of IL-13 in experimental asthma.
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