Allergen-driven epithelial genes in asthma pathogenesis

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Bronchial asthma is a chronic inflammatory disorder of the lung that has reached epidemic proportions over the last few decades, underscoring the need fora better understanding of the molecular basis of disease. Numerous experimental, clinical and genetic studies suggest that the development of the asthmatic diathesis is dependent upon CD4+T cell production of the Th2 cytokine, interleukin-13. Despite intensive efforts, the mechanisms by which IL-13 mediates the manifestations of disease remain unknown. Utilizing a gene profiling approach to identify novel downstream targets of IL-13, we have identified a group of genes belonging to the newly described chitinase family (AMCase, YM-1), which are highly up-regulated in the lungs of allergen- and IL-13-challenged mice. Importantly, we find that AMCase mRNA levels are increased in nasal biopsies of from patients with asthma. Moreover, asthma-related traits in humans have been linked to regions of chromosome 1 containing the chitinase gene cluster. Although virtually nothing is known about the functions of the chitinase genes, or their exact roles in Th2 immune responses they have been shown to be elevated in a variety of inflammatory diseases, to induce eosinophilic inflammation and chemokine secretion, and to directly induce fibroblast growth. Thus, we plan to critically test the hypothesis that chitinase family members play an important role in asthma pathogenesis and that polymorphisms in the AMCase gene may contribute to the development of allergic asthma in humans. The specific aims are: 1) to investigate the unique and/or overlapping roles of AMCase and YM-1 in IL-13-induced airway inflammation and development of AHR, by modulating their expression in vivo utilizing several complementary approaches; 2) to determine the role of chitinases in allergen-induced sub-epithelial fibrosis in mice, we will assess tissue fibrosis, collagen accumulation, and the production of pro-fibrotic mediators in vivo and in vitro; 3) to identify and characterize potential functional polymorphisms in the gene encoding the chitinase family member, AMCase, in two well-characterized cohorts of asthmatic children from the Cincinnati region. Lastly, we will assess gene-gene interactions between AMCase and IL-13 and its receptor, IL-4Ra. The power of the murine model to assess the functional role of these genes in combination with identification of functional polymorphisms associated with asthma/atopy in our human cohorts will give us new insight into the relationship between these novel gene candidates and atopic asthma and empower the search for novel therapeutics.