The concept of the pathogenesis of asthma has evolved from the 1960s viewpoint of asthma as being a disorder having a primary defect in lung smooth muscle requiring treatment with beta agonists, to the current paradigm of asthma being a disease primarily due to airway inflammation. The goal of this UCSD AADCRC U19 program is to challenge the current paradigm that asthma is solely a disease of airway inflammation which induces structural changes in the airway, by proposing that asthma is a disease of both lung structural cells (smooth muscle) as well as airway inflammation (in particular controlled by T cells and ILC2) and that developing therapeutic strategies to target both airway structural cells and immune/inflammatory cells is needed to control severe asthma with airway remodeling. In this regard, atopic dermatitis, is a good example of a disease that is part of the atopic march to asthma which is characterized not only by skin inflammation, but also in a subset by a genetic defect in a skin structural gene filaggrin. Similarly, we hypothesize that there are lung structural gene defects in asthma that predispose to airway remodeling in asthma. In support of this hypothesis preliminary data in Project 1 (Broide) provides evidence that ORMDL3, a gene highly linked to childhood asthma and severe asthma, when expressed in smooth muscle contributes to smooth muscle remodeling in the absence of an exogenous inflammatory stimulus. Thus, the goal of the program is to demonstrate that airway remodeling in asthma may be mediated by a combination of pathways intrinsic to structural cells in the lung (e.g. ORMDL3 expressed in smooth muscle)(Broide, Project 1), interacting with exogenous immune (T cells) and inflammatory (ILC2/macrophage) pathways to induce smooth muscle, fibroblast and epithelial remodeling. In this regard, our preliminary data demonstrates that LIGHT and TL1A (derived from T cells/macrophages) drives smooth muscle, fibroblast and epithelial remodeling (Croft, Project 2), while T cells and ILC2 express CD6 which interacts with ALCAM on smooth muscle to mediate bidirectional signaling activating T cells and ILC2 to proliferate and express pro-inflammatory cytokines, as well as smooth muscle to proliferate (Doherty, Project 3). The hypothesis in each project will be tested in human asthma clinical samples (sputum, blood, endobronchial biopsy, as well as post mortem lung and lung lymph nodes) provided by Human Asthma Clinical Core B directed by David Broide (UCSD), and co- investigators Richard Kurten (University of Arkansas) and Qutayba Hamid (McGill University).

Public Health Relevance

This University of California San Diego proposal seeks to increase our understanding of how the muscle layer around the bronchial tubes increase in amount in asthma. The increased amount of muscle around the bronchial tubes narrows the bronchial tube and causes difficulty breathing. Understanding how the muscle layer increases in amount around bronchial tubes may provide new ways of treatment to prevent it from increasing in amount.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
Program Officer
Dong, Gang
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University of California, San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Unno, Hirotoshi; Miller, Marina; Rosenthal, Peter et al. (2018) Activating transcription factor 6? (ATF6?) regulates airway hyperreactivity, smooth muscle proliferation, and contractility. J Allergy Clin Immunol 141:439-442.e4
Miller, Marina; Vuong, Christine; Garcia, Meghan Farrell et al. (2018) Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? J Allergy Clin Immunol 142:706-709.e4
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Herro, Rana; Shui, Jr-Wen; Zahner, Sonja et al. (2018) LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. J Exp Med 215:415-422
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2018) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol 142:207-218.e6
White, Andrew A; Doherty, Taylor A (2018) Role of group 2 innate lymphocytes in aspirin-exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 32:7-11
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2018) TNF activity and T cells. Cytokine 101:14-18
Karta, Maya R; Rosenthal, Peter S; Beppu, Andrew et al. (2018) ?2 integrins rather than ?1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung. J Allergy Clin Immunol 141:329-338.e12
Mehta, A K; Doherty, T; Broide, D et al. (2018) Tumor necrosis factor family member LIGHT acts with IL-1? and TGF-? to promote airway remodeling during rhinovirus infection. Allergy 73:1415-1424
Doherty, Taylor A; Broide, David H (2018) Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. J Allergy Clin Immunol 141:1587-1589

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