Allergen-driven epithelial genes in asthma pathogenesis

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

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