PROJECT SUMMARY/ABSTRACT The applicant's goals are to develop the necessary skills to become an independent translational researcher in the area of neonatal/pediatric asthma. Childhood asthma developing early in life is a major healthcare burden. Corticosteroids (CS) are used therapeutically, but compared to adults, children require higher CS doses, and some develop CS resistance with greater airway remodeling that is difficult to treat. The mechanisms underlying CS insensitivity in developing airway are largely unknown. Airway smooth muscle (ASM) is a key cell type in asthma, and exhibits hyperreactivity (AHR), proliferation, and remodeling in response to inflammation. There is currently little information on how developing ASM contributes to neonatal/pediatric asthma, or to CS resistance. The overall hypothesis is that Th1 inflammation (TNF?, IFN?) induces CS insensitivity in developing airway by disrupting glucocorticoid receptor expression and signaling, leading to enhanced ASM proliferation and remodeling. In terms of potential therapy, there is increasing evidence for Vitamin D (VitD) enhancing CS sensitivity, but little to no information on underlying mechanisms, particularly in developing airway (a second focus of this proposal). Via 3 Aims, the applicant will progressively build towards research independence investigating CS insensitivity in neonatal/pediatric asthma: Aim 1 (K99 Phase): Using an in vitro model of Th1 induced CS insensitivity, determine mechanisms by which inflammation inhibits GR signaling and activity in developing human ASM. Aim 2 (K99/R00 Phases): Using an in vitro model of Th1 induced CS insensitivity determine mechanisms by which VitD enhances GR signaling in developing human ASM. Specific Aim 3 (R00 Phase): In novel CS-insensitive vs. ?sensitive newborn mouse models of allergic airway inflammation, determine interactions between CS and calcitriol in alleviating AHR and remodeling. The mentored phase will examine how Th1 cytokines disrupt CS signaling in human fetal ASM (18-22 week gestation). The applicant will receive training in investigating cellular, molecular, and epigenetic mechanisms related to glucocorticoid receptor signaling via an in vitro model of neonatal CS insensitivity involving Th1 cytokines. Complementary didactic, intellectual, and professional training will help prepare the applicant for the R00 phase where he will examine mechanisms relating to how VitD may enhance CS sensitivity in developing ASM using in vitro and novel in vivo neonatal mouse models of CS insensitivity. Together, these novel studies will enhance current understanding of how inflammation early in life disrupts glucocorticoid receptor signaling, and will identify the potential for VitD to improve CS sensitivity. The applicant will be mentored by senior, established investigators with substantial expertise in ASM physiology, lung immunology, glucocorticoid signaling, and asthma. Importantly, this project will provide a foundation for the applicant to establish an independent research program in neonatal/pediatric airway disease.
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