Airway remodeling is the term applied to the structural changes observed in the airway in asthma. Although current NIH guidelines recommend maintaining a goal of normal lung function in asthma, current therapeutic strategies do not specifically target airway remodeling as the cellular and molecular mechanisms that result in remodeling are not well defined and thus therapeutic targets are not well understood. Thus, there is an important need to identify mechanisms by which airway remodeling is mediated so that potential novel therapies could be directed at these pathways. In addition, characterization of these pathways could lead to the development of non-invasive blood or sputum biomarkers to identify, monitor, and perhaps subset, patients with asthma and remodeled airways. This UCSD AADCRC proposal will be directed by David Broide (Professor of Medicine) and include three projects (Broide, Croft, Zuraw) that will investigate mechanisms of airway remodeling in asthmatics exposed to allergen and rhinovirus common triggers of asthma. Thus, the overall hypothesis that will be explored in all three projects is that exposure to allergen triggers expression of inflammatory and remodeling pathways in allergic asthmatics that are exacerbated by exposure to respiratory viruses such as rhinovirus. The specific hypothesis that will be explored in each project and that will be driven by samples from asthmatics, is that the innate immune response (airway epithelium, macrophages, natural helper cells) play an important role in initiating and perpetuating the inflammatory and airway remodeling response to environmental triggers in allergic asthmatics. The three interrelated projects will focus on """"""""Innate inflammation and airway remodeling"""""""" (Broide, Project 1), """"""""TNF-R family members, inflammation and remodeling"""""""" (Croft, Project 2), and """"""""Epithelial GILZ inflammation and remodeling"""""""" (Zuraw, Project 3) and be supported by Administrative Core A, and """"""""Asthma Clinical Core B"""""""" which will be a source of sputum, BAL, endobronchial biopsy, and blood samples from asthma and control subjects provided by investigators in Core B (Ramsdell, Harrell, and Thistlethwaite, UCSD;Proud and Leigh, University of Calgary;and Hamid, McGill University). An lOFM Core is also proposed as requested by the RFA.

Public Health Relevance

Respiratory tract viral infections and inhalation of airborne allergens such as cat and dust mite may result in damage and scarring of the bronchial tubes in susceptible asthmatics. This project will provide increased understanding of the cause of this scarring and suggest potential ways to identify asthmatics at risk for developing scarring of their lungs, or potential new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-07
Application #
8306790
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Dong, Gang
Project Start
2006-07-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$1,427,345
Indirect Cost
$257,295
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Das, Sudipta; Miller, Marina; Beppu, Andrew K et al. (2016) GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci U S A 113:13132-13137
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 137:278-88.e6
Rajan, Jessica; Newbury, Robert O; Anilkumar, Arjun et al. (2016) Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J Allergy Clin Immunol 137:147-56.e8
Herro, Rana; Croft, Michael (2016) The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF Superfamily member 14). Pharmacol Res 104:151-5
Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2016) TNF activity and T cells. Cytokine :
Rawson, Renee; Yang, Tom; Newbury, Robert O et al. (2016) TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J Allergy Clin Immunol 138:791-800.e4
Miller, Marina; Esnault, Stephane; Kurten, Richard C et al. (2016) Segmental allergen challenge increases levels of airway follistatin-like 1 in patients with asthma. J Allergy Clin Immunol 138:596-599.e4
Karta, Maya R; Broide, David H; Doherty, Taylor A (2016) Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease. Curr Allergy Asthma Rep 16:8
Kim, Alexander S; Doherty, Taylor A; Karta, Maya R et al. (2016) Regulatory B cells and T follicular helper cells are reduced in allergic rhinitis. J Allergy Clin Immunol 138:1192-1195.e5

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