Persistent asthma is often accompanied by airway remodeling that accounts for a disproportionate fraction of asthma morbidity and mortality. The epithelium is thought to play an integral role in airway remodeling linked to rhinovirus-induced asthma exacerbations and glucocorticoid resistance. Glucocorticoid-induced leucine zipper (GILZ) is a pluripotent endogenous anti-inflammatory protein that inhibits NF-KB, AP-1 and MAPK signaling and that is reduced in asthmatic epithelial cells. The overall hypothesis is that the extent of asthmatic remodeling is strongly influenced by the expression of GILZ in airway epithelial cells, and that therapeutic strategies to increase GILZ may prevent remodeling even in asthmatic patients with glucocorticoid resistance.
Three aims are proposed:
Aim #1 will address whether decreased expression of GILZ contribute to more severe asthma exacerbations and airway remodeling;
Aim #2 will address whether glucocorticoid resistance involves a failure of glucocorticoids to trans-activate GILZ mRNA expression;
and Aim #3 will address whether therapeutic strategies to increase GILZ via a non-glucocorticoid mechanism decrease airway inflammation and protect patients from asthma exacerbations and airway remodeling. The proposed work will heavily utilize human asthmatic subjects from the Asthma Clinical Core. The approach will start with the analysis of primary bronchial epithelial cells from either asthmatic (or normal) subjects who are challenged with relevant allergen or rhinovirus or asthmatic subjects who are glucocorticoid resistant (or sensitive), then seek mechanistic extensions using normal human airway epithelial cells and finally a unique mouse strain in which GILZ has been genetically deleted from airway epithelial cells. GILZ is an anti-inflammatory protein, and the data from these experiments will complement the pro-inflammatory data from the same samples in the other two projects in this program project. By the end of these studies, the importance of GILZ as rheostat for allergic airway inflammation will be defined, and its role in glucocorticoid resistance defined. The therapeutic potential of non-glucocorticoid based approaches to increase GILZ in airway epithelial cells will be assessed and provides the most important long-term goal of the project.

Public Health Relevance

Asthma exacerbations and glucocorticoid resistance have been linked to increased airway remodeling and also define severe asthma, which is responsible for an overwhelming percentage of both asthma costs and asthma morbidity. GILZ is likely to play an important role in both asthma exacerbations and glucocorticoid resistance. The studies to increase GILZ expression through novel interventions could provide an entirely new therapeutic direction to meet the challenges of severe asthma and airway remodeling.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Doherty, Taylor A; Broide, David H (2017) Pathways to limit group 2 innate lymphoid cell activation. J Allergy Clin Immunol 139:1465-1467
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2017) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol :
Lund, Sean J; Portillo, Alex; Cavagnero, Kellen et al. (2017) Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation. J Immunol 199:1096-1104
Cavagnero, Kellen; Doherty, Taylor A (2017) Cytokine and Lipid Mediator Regulation of Group 2 Innate Lymphoid Cells (ILC2s) in Human Allergic Airway Disease. J Cytokine Biol 2:
Song, Dae Jin; Miller, Marina; Beppu, Andrew et al. (2017) Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation. J Immunol 199:2215-2224
Miller, Marina; Tam, Arvin B; Mueller, James L et al. (2017) Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. J Immunol 198:3017-3022
Eastman, Jacqueline J; Cavagnero, Kellen J; Deconde, Adam S et al. (2017) Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 140:101-108.e3
Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2017) Oroscomucoid like protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide. J Allergy Clin Immunol 139:1373-1376.e4
Croft, Michael; Siegel, Richard M (2017) Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13:217-233
Mehta, Amit K; Duan, Wei; Doerner, Astrid M et al. (2016) Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. J Allergy Clin Immunol 137:278-288.e6

Showing the most recent 10 out of 96 publications