PROJECT SUMMARY Asthma remains a significant healthcare burden for children and has a long-term impact on their development and health. Inhaled corticosteroids are key for managing asthmatic symptoms and disease progression. However, children with severe asthma are insensitive or resistant corticosteroid therapies, leading to the need for systemic use at high doses. Airway smooth muscle (ASM) is a key structural cell that regulates airway function and tone. In severe pediatric asthma, airway inflammation, hyperresponsiveness (AHR), and remodeling continues despite aggressive corticosteroid treatments. Yet the underlying biological mechanisms of corticosteroid insensitivity or resistance, particularly in ASM, remain undefined. Studies have reported associations between Th1 inflammation, as indicated by increased Th1 lymphocyte airway infiltration and IFN? levels, and severe asthma. Additionally, we recently showed that combined exposure to IFN? and TNF? uniquely induces corticosteroid resistance in ASM. These data have led us to hypothesize that IFN? and TNF? interactions enable pro-inflammatory signaling pathways, notably NF?B and JAK/Stat1, to remain activated in the presence of corticosteroids. Via 2 Specific Aims, we will use novel mouse and human models of corticosteroid resistance to examine airway inflammation, hyperresponsiveness (AHR), and remodeling in ASM. Specific Aim 1 will test the hypothesis that IFN? enhances airway hyperresponsiveness and remodeling in ASM during steroid resistant allergic airway inflammation. While Specific Aim 2 will test the hypothesis that combined exposure to IFN? and TNF? opens chromatin structure, leading to corticosteroid resistance in human pediatric ASM. This proposal will involve using cellular, molecular, and bioinformatic approaches to understand how interactions between IFN? and TNF? enhance Ca2+ regulatory mechanisms and transcriptional regulation in ASM. Furthermore, we will examine whether targeting the JAK/Stat pathway can improve corticosteroid sensitivity in ASM and improve airway function. These novel studies will expand the current understanding of how airway structural cells, such as ASM, develop corticosteroid resistance while also beginning to define mechanisms that mediate corticosteroid resistance in severe pediatric asthma.
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