Epithelial GILZ in Inflammation and Remodeling

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PROJECT SUMMARY (See instructions): Persistent asthma is often accompanied by airway remodeling that accounts for a disproportionate fraction of asthma morbidity and mortality. The epithelium is thought to play an integral role in airway remodeling linked to rhinovirus-induced asthma exacerbations and glucocorticoid resistance. Glucocorticoid-induced leucine zipper (GILZ) is a pluripotent endogenous anti-inflammatory protein that inhibits NF-KB, AP-1 and MAPK signaling and that is reduced in asthmatic epithelial cells. The overall hypothesis is that the extent of asthmatic remodeling is strongly influenced by the expression of GILZ in airway epithelial cells, and that therapeutic strategies to increase GILZ may prevent remodeling even in asthmatic patients with glucocorticoid resistance. Three aims are proposed: Aim #1 will address whether decreased expression of GILZ contribute to more severe asthma exacerbations and airway remodeling; Aim #2 will address whether glucocorticoid resistance involves a failure of glucocorticoids to trans-activate GILZ mRNA expression; and Aim #3 will address whether therapeutic strategies to increase GILZ via a non-glucocorticoid mechanism decrease airway inflammation and protect patients from asthma exacerbations and airway remodeling. The proposed work will heavily utilize human asthmatic subjects from the Asthma Clinical Core. The approach will start with the analysis of primary bronchial epithelial cells from either asthmatic (or normal) subjects who are challenged with relevant allergen or rhinovirus or asthmatic subjects who are glucocorticoid resistant (or sensitive), then seek mechanistic extensions using normal human airway epithelial cells and finally a unique mouse strain in which GILZ has been genetically deleted from airway epithelial cells. GILZ is an anti-inflammatory protein, and the data from these experiments will complement the pro-inflammatory data from the same samples in the other two projects in this program project. By the end of these studies, the importance of GILZ as rheostat for allergic airway inflammation will be defined, and its role in glucocorticoid resistance defined. The therapeutic potential of non-glucocorticoid based approaches to increase GILZ in airway epithelial cells will be assessed and provides the most important long-term goal of the project.