This proposal seeks to renew an Asthma and Allergic Diseases Cooperative Research Center that has been focusing on the mechanisms of initiation and persistence of allergic asthma. During the course of these studies and earlier work done in our laboratories and multiple other labs, it has become clear that two cytokines, IL-13 and IL-17, make important contributions to the most critical functional endpoints in asthma (airway hyperresponsiveness and mucus metaplasia) through spatially and temporally restricted effects on airway epithelial cells and airway smooth muscle. In the current proposal, individual projects will focus on how each cytokine regulates airway epithelial cell differentiation and mucous metaplasia, how these cytokines work alone and in combination to regulate contractility of airway smooth muscle, and the dynamic behavior of the cells that generate these cytokines in the airway wall. Each of these projects will have a major focus on human asthma and will rely heavily on a Clinical Subject and Biospecimen Core that will provide basic characterization of airway physiology, evidence for IL-13 and IL-17 bioactivity, and samples of bronchoalveolar lavage fluid, epithelial brushings and airway biopsies for use in each of the 3 projects. These samples and clinical information will be obtained from subjects in 3 cohorts, ACE, RITA and SARP, that will enroll subjects for segmental allergen challenge, subjects with mild-to-moderate asthma undergoing a trial of inhaled corticosteroids and patients with severe asthma, respectively. Through the proposed studies we hope to gain new insights into the dynamic effects of IL-13 and IL-17 in asthma, to develop better tools to characterize subsets of patients with asthma and to improve the prospects for targeted therapy of this disease.

Public Health Relevance

This proposal will examine how two cytokines, IL-13 and IL-17, specifically effect airway epithelial cells and airway smooth muscle to contribute to the most important causes of symptoms in patients with asthma. By examining the pathways responsible for these effects and focusing on human patients and tissues we hope to identify new strategies for treating this common and often devastating disease. Project 1: IL-13/17-Regulated Airway Epithelial miRNAs in Asthma Project Leader: David Erle DESCRIPTION (as provided by applicant): 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 of the 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 #
5U19AI077439-07
Application #
8607878
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Program Officer
Dong, Gang
Project Start
2008-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$1,680,602
Indirect Cost
$564,591
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sherenian, M G; Cho, S H; Levin, A et al. (2017) PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort. Clin Exp Allergy 47:1150-1158
Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin et al. (2017) Targeting integrin ?5?1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest 127:365-374
Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812
Yi, L; Cheng, D; Zhang, K et al. (2017) Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis. Mucosal Immunol 10:1491-1503
Reboldi, Andrea; Arnon, Tal I; Rodda, Lauren B et al. (2016) IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches. Science 352:aaf4822
Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430
Sen, Debasish; Jones, Stephen M; Oswald, Erin M et al. (2016) Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung. PLoS One 11:e0165064
Meliopoulos, Victoria A; Van de Velde, Lee-Ann; Van de Velde, Nicholas C et al. (2016) An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens. PLoS Pathog 12:e1005804
McAleer, Jeremy P; Nguyen, Nikki L H; Chen, Kong et al. (2016) Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. J Immunol 197:97-107
Thanabalasuriar, Ajitha; Neupane, Arpan S; Wang, Jing et al. (2016) iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation. Cell Rep 16:3260-3272

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