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 (TNFa, 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.