PROJECT SUMMARY Patients with chronic obstructive pulmonary disease often show airway epithelial remodeling including basal cell hyperplasia, and goblet cell and squamous cell metaplasia. Such pathologic changes profoundly affect the outcome of respiratory infection as airway epithelium plays a crucial role in defining the innate and adaptive immunity in the lungs. Airway basal cells are the specialized stem cells and regenerate functional mucociliary- differentiated airway epithelium upon injury. The fact that COPD patients show airway epithelial remodeling indicate dysregulated repair mechanisms in airway basal cells. Our research suggests that quercetin, a natural polyphenol reverses airway epithelial remodeling in a mouse model of COPD. Our preliminary studies indicate that quercetin reprograms dysregulated repair pathways in COPD basal cells leading to regeneration of normal airway epithelium. We conducted transcriptomic analysis of airway basal cells from healthy non-smokers and COPD subjects and COPD basal cells treated with quercetin. Results from this microarray indicated dysregulation of genes involved in tissue development and epithelial differentiation in COPD cells. Intriguingly, the topmost differentially regulated genes in both these pathways are genes involved in lung morphogenesis HOXA1 and HOXB2. In normal basal cells, HOXA1 is highly expressed in basal cells, while HOXB2 expression increased at two weeks of culturing and correlated with polarization of cells, a prerequisite step in differentiation. COPD basal cells showed significantly reduced expression of both HOXA1 and HOXB2 and quercetin treatment increased expression of both genes. Based on these observations, we will examine a novel hypotheses that quercetin via modulation of HOXA1 and HOXB2 corrects the dysregulated repair mechanisms, thus improving immune responses to respiratory infections and lung function in COPD. In Specific Aim 1, we will determine the role of HOXA1 and HOXB2 in the regeneration of airway epithelium, and whether quercetin corrects the dysregulated repair mechanism in COPD by modulation of these HOX genes. In Specific Aim 2, we will examine the molecular mechanisms by which quercetin-induced HOXA1 and HOXB2 participates in the regeneration of airway epithelium. In Specific Aim 3, we will examine whether quercetin-induced HOXA1 and HOXB2 participate in limiting exaggerated innate immune responses to rhinovirus infection and prevent progression of lung disease in COPD. Finally, we will confirm whether quercetin treatment reduces airway epithelial remodeling in COPD patients and correlate with the expression of HOXA1 and HOXB2. Completion of these studies will provide important insight into airway epithelial regeneration and the mechanisms by which quercetin reduces airway epithelial remodeling in COPD.