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)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-09
Application #
8711190
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chang, Jinny E; Doherty, Taylor A; Baum, Rachel et al. (2014) Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J Allergy Clin Immunol 133:899-901.e3
Cho, Jae Youn; Doshi, Ashmi; Rosenthal, Peter et al. (2014) Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 59:10-6
Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90
Nonaka, Motohiro; Bao, Xingfeng; Matsumura, Fumiko et al. (2014) Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites. Proc Natl Acad Sci U S A 111:8173-8
Ge, Xiao Na; Ha, Sung Gil; Rao, Amrita et al. (2014) Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model. Glycobiology 24:715-27
Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2014) ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. J Immunol 192:3475-87
Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2014) Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol 15:767-76
Cho, Jae Youn; Rosenthal, Peter; Miller, Marina et al. (2014) Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis. Int Immunopharmacol 18:35-42
Suzukawa, Maho; Miller, Marina; Rosenthal, Peter et al. (2013) Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice. J Immunol 190:5939-48
Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68

Showing the most recent 10 out of 57 publications