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.
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.
|Myers, Rachel A; Scott, Nicole M; Gauderman, W James et al. (2014) Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet 23:5251-9|
|Poole, Alex; Urbanek, Cydney; Eng, Celeste et al. (2014) Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. J Allergy Clin Immunol 133:670-8.e12|
|Travis, Mark A; Sheppard, Dean (2014) TGF-* activation and function in immunity. Annu Rev Immunol 32:51-82|
|Zhao, Wenxue; Pollack, Joshua L; Blagev, Denitza P et al. (2014) Massively parallel functional annotation of 3' untranslated regions. Nat Biotechnol 32:387-91|
|Fejerman, Laura; Ahmadiyeh, Nasim; Hu, Donglei et al. (2014) Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun 5:5260|
|Broz, Miranda L; Binnewies, Mikhail; Boldajipour, Bijan et al. (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638-52|
|Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika et al. (2014) Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One 9:e104396|
|Bhattacharya, Mallar; Sundaram, Aparna; Kudo, Makoto et al. (2014) IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction. J Clin Invest 124:4895-8|
|Thakur, Neeta; McGarry, Meghan E; Oh, Sam S et al. (2014) The lung corps' approach to reducing health disparities in respiratory disease. Ann Am Thorac Soc 11:655-60|
|Thakur, Neeta; Martin, Melissa; Castellanos, Elizabeth et al. (2014) Socioeconomic status and asthma control in African American youth in SAGE II. J Asthma 51:720-8|
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