Genome wide association studies have identified strong linkage between chromosome 17q21 and asthma. The focus of this proposal is on ORMDL-3, a protein localized to chromosome 17q21, which has been highly linked to asthma in several genome wide association studies. The investigation of the function of ORMDL-3 in the lung in asthma in this proposal will be enhanced by the development of unique reagents in the investigators lab (e.g. universal and cell specific ORMDL-3 transgenic and ORMDL-3 deficient mice;development of antibody to ORMDL to perform immunohistological). Based on our preliminary data we hypothesize that allergen induced ORMDL-3 expression regulates expression of multiple epithelial pathways (inflammation, remodeling, repair), as well as the ER ATF6 pathway which together play an important role in the pathogenesis of asthma. The studies proposed will use in vitro (knock down or over-expression of ORMDL-3 in lung cells) and in vivo studies (ORMDL-3 transgenic and ORMDL-3 deficient mice) to determine the role of ORMDL3 in the pathogenesis of allergen and rhinoviral induced asthma.

Public Health Relevance

Although the gene ORMDL-3 on chromosome 17q21 is highly associated with the development of asthma, little is known about the function of ORMDL-3 and how it may contribute to the development of asthma. In this study we will use lung cells from mice and humans as well as a mouse model of asthma to determine how ORMDL-3 causes asthma. This may provide insight into novel treatments for asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI107779-01
Application #
8576660
Study Section
Special Emphasis Panel (ZRG1-IMM-C (02))
Program Officer
Minnicozzi, Michael
Project Start
2013-05-15
Project End
2018-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$364,250
Indirect Cost
$129,250
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
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
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
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
Miller, Marina; Beppu, Andrew; Rosenthal, Peter et al. (2015) Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M. J Immunol 195:3546-56
Rawson, Renee; Anilkumar, Arjun; Newbury, Robert O et al. (2015) The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis. PLoS One 10:e0144651
Beppu, Lisa; Yang, Tom; Luk, Michelle et al. (2015) MMPs-2 and -14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy. J Pediatr Gastroenterol Nutr 61:194-9

Showing the most recent 10 out of 19 publications