Airway epithelial cells play a major role in asthma. We recently discovered striking abnormalities in epithelial expression of micro-RNAs (miRNAs) in most subjects with asthma. The overall goal of this project is to understand the nature, causes and consequences of altered epithelial miRNA expression in asthma. Our preliminary studies suggest that IL-13 is responsible for miRNA abnormalities seen in many asthmatics. IL- 17 also alters epithelial miRNA expression, a finding that may be especially relevant for individuals with severe asthma. Epithelial miRNA abnormalities were only modestly reversed by corticosteroid treatment, suggesting that miRNAs may represent novel therapeutic targets for steroid-resistant asthma. Some ofthe miRNAs that are changed in asthma are known to regulate mucociliary differentiation in related systems, but the functional consequences of altered epithelial miRNA expression in asthma remain to be determined. This project has 3 specific aims: 1) Identify epithelial miRNAs that are altered in severe asthma and relate their expression to IL-13 and IL-17 production and mucous metaplasia in the airway, 2) Determine how IL-13 and IL-17 affect miRNA levels in human bronchial epithelial (HBE) cells, and 3) Determine how selected IL-13- and IL-17-regulated miRNAs affect HBE cell gene expression, differentiation and function. These studies will impact asthma research by identifying novel pathophysiologic mechanisms, providing new tools for molecular phenotyping of asthma subsets, and discovering novel therapeutic targets.

Public Health Relevance

Epithelial cells line the airways and play an important role in asthma. Micro-RNAs regulate gene expression. We will identify the nature, causes and consequences of changes in airway epithelial cell micro-RNAs in asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI077439-06
Application #
8468273
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$416,407
Indirect Cost
$141,445
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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