Chronic persistent asthma has been linked to both ongoing airway inflammation and airway remodeling.The relationship between airway inflammation and remodeling has remained uncertain; but there isevidence that corticosteroid therapy does not prevent the development of airway remodeling. Thus, there isa major impetus to understand the pathogenesis of airway remodeling at a more fundamental level. One ofthe critical components of airway remodeling is the generation of myofibroblasts. Myofibroblasts contributeboth to the enhanced deposition of matrix protein including types I and III collagens as well as to thecontractile apparatus. Relatively little is known about the origin of myofibroblasts involved in asthma. Threepotential sources of airway myofibroblasts are activation of resident lung fibroblasts, recruitment of bonemarrow fibroblast stem cells that differentiate into fibroblasts and transition or transdifferentiation of airwayepithelial cell into myofibroblasts. Studies in other organs, particularly the kidney, have shown that epithelialto mesenchymal transition (EMT) is a major source of myofibroblasts following injury or trauma. Ourhypothesis is that airway epithelial cells in chronic asthma establish a local milieu that promotes transition ofepithelial cells to myofibroblasts, and that this represents a significant component of airway remodeling. Animportant corollary of this hypothesis is that changing the local milieu can promote myofiblast to epithelialtransition, and thereby improve remodeling.To test this hypothesis, we propose the following specific aims: 1: Assess the mechanisms underlyingepithelial-mesenchymal transition (EMT) in airway epithelial cells; 2) Analyze the regulation of epithelialmesenchymaltransition in airway epithelial cells; and 3) Explore the relationship between epithelialmesenchymaltransition and in vivo airway remodeling in patients with chronic asthma.These studies will directly address a fundamental mechanism by which the airway may undergoremodeling during chronic asthma. Because the pathways leading to epithelial to mesenchymal transitionare subject to regulation by current and future medications, defining the molecular steps in the process oftransition will provide guidance for future efforts to limit remodeling. Finally, development of a biomarker forremodeling will significantly enhance the ability to monitor these therapeutic efforts.
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