Enhancing Corticosteroid Sensitivity in Neonatal and Pediatric Lung Disease

Research Inst Nationwide Children'S Hosp, Columbus OH

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Abstract

PROJECT DESCRIPTION Children with severe asthma are resistant or refractory to corticosteroid-based therapies and experience significantly more asthmatic exacerbations and hospitalizations than those with mild asthma. Although specific inflammatory pathways are thought to contribute to corticosteroid resistance, little is known about how inflammation, such as Th17 inflammation, promotes corticosteroid resistance in pediatric asthma. Airway smooth muscle cells (ASM) play a key role in the airway hyperresponsiveness, airflow obstruction, and remodeling in patients with pediatric asthma. Recent studies demonstrate that IL-17, the effector cytokine in Th17 inflammation, augments inflammation and remodeling in ASM. Yet the effects of IL-17 in the context of steroid resistance in ASM are largely unexplored. We hypothesize that the effects of IL-17 on inflammation and remodeling in pediatric ASM are corticosteroid resistant, allowing production of inflammatory mediators and ASM remodeling to persist in the presence of corticosteroids. This hypothesis will be explored via 2 Aims: Supplement Aim 1: Determine the effects of IL-17A on pediatric ASM inflammation and remodeling in the presence of corticosteroids; Supplement Aim 2: Determine the role of IL-17A in a mouse model of corticosteroid-resistant allergic airway inflammation. Studies in Aim 1, will examine the effect of IL-17 on inflammation, remodeling (proliferation, migration), and glucocorticoid receptor activity in human pediatric ASM. In Aim 2, the role of Th17 inflammation in airway inflammation and remodeling will be examined in mice sensitized and challenged with allergens and treated with corticosteroids. As an extension but within the scope of the parent R00, the Supplement will provide a postbaccalaureate student with the necessary scientific and professional training to pursue a career as a biomedical researcher. The proposed studies are aligned with a comprehensive mentoring plan that aims to enable the postbaccalaureate student to be highly competitive for PhD or MD/PhD programs and prepared for the rigors of graduate and/or medical school. Together, these novel studies will help improve the understanding of underlying mechanisms of steroid resistance in pediatric asthma, while facilitating the development of an aspiring biomedical scientist.