Abstract

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.

  Funding Agency

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

  Institution

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

  Publications

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
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
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
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
Köster, Stefan; Klevorn, Thais; Papavinasasundaram, Kadamba et al. (2018) Consequence of enhanced LC3-trafficking for a live, attenuated M. tuberculosis vaccine. Vaccine 36:939-944
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
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
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
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

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