The focus of this proposal is on ORMDL3 a gene on chromosome 17q21, which has been highly linked to human asthma in several genome wide association studies. As ORMDL3 is highly expressed in CD4+ cells, in this proposal we seek to determine how ORMDL3 influences CD4+ cell function, allergic inflammation, and asthma. Although the linkage of chromosome 17q21 to asthma is very well established, the biologic mechanism(s) underpinning this association in lung cells pertinent to the pathogenesis of asthma is not as well understood and is the focus of this proposal. In addition as there are at least 9 genes located in this region on chromosome 17q21 understanding the biology of each of these genes individually is important to understanding how this region influences the development of asthma. As the SNP linking ORMDL3 to asthma is associated with increased levels of ORMDL3 expression, we generated universal ORMDL3 transgenic (TG) mice that express increased levels of human ORMDL3 (hORMDL3) and demonstrated that they spontaneously (in the absence of allergen exposure) develop significantly increased ASM and increased AHR, major features of asthma. In addition to this important baseline effect of ORMDL3 in ASM on AHR, ORMDL3 also plays a significant role in enhancing Th2 responses and AHR as demonstrated in our studies of allergen challenged universal hORMDL3 TG mice. Thus, the focus of this proposal is to increase our understanding of how ORMDL3 expressed in CD4+ T lymphocytes enhances Th2 responses to allergen challenge. In this grant proposal we propose to demonstrate that CD4+ cells (mouse and human) expressing increased levels of ORMDL3 have enhanced Th2 responses in vitro and in vivo to house dust mite (HDM) allergen, and using proteomic and RNAseq approaches plan to identify downstream pathways in HDM tetramer positive CD4+ cells that mediate this ORMDL3 effect. Targeted knockdown or overexpression of pathways identified to be downstream of ORMDL3 will demonstrate their contribution to the function of CD4 cells. Finally, we are using single base editing to edit SNPs linked to ORMDL3 to determine which SNPs functionally regulate levels of ORMDL3, Th2 cytokines, and downstream pathways of ORMDL3.

Public Health Relevance

Although the gene ORMDL3 is highly associated with the development of asthma, little is known about the function of ORMDL3 and how it may contribute to the development of asthma. In this study we will use immune cells cells from humans as well as a mouse model of asthma to determine how ORMDL3 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 #
2R01AI107779-06A1
Application #
9885992
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Minnicozzi, Michael
Project Start
2013-05-15
Project End
2025-02-28
Budget Start
2020-03-20
Budget End
2021-02-28
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
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
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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
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
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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