The overall goal of this AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and to use that information to prevent this type of disease. We combine expertise in airway as well as gut and skin epithelial cell biology, and we use cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that ask, first, how airway epithelial cells mediate effective antiviral defense under one condition but asthma under another (Project 1), second, how airway epithelial cells remodel towards an overabundance of mucous cells in post-viral and allergic asthma (Project 2), and third, how epithelial injury in the skin triggers the march from atopic dermatitis to asthma (Project 3). Each project addresses the respective question with a novel but overlapping molecular approach to mechanism and takes advantage of a breakthrough discovery to set a new scientific paradigm for the system under study. Thus, Project 1 unravels a new IFN signaling pathway that offers improved protection against viral infection and post-viral asthma and is specific to the airway epithelial cell barrier;Project 2 dissects a new pathway for autophagy proteins to support proper mucous cell function and prevent mucous cell metaplasia in the airway in a manner reminiscent of the intestinal epithelial barrier;and Project 3 defines a new TSLP production and secretion pathway that drives airway inflammation based on its expression in the skin epithelial barrier. Each Project is constructed so that the first aim will establish a basic pathogenic mechanism using cell and mouse models that are shared among projects and supported by the Cores for tissue and cell processing (Core C) and mouse models (Core D). In turn, each Project will conduct a second aim to validate and translate its findings using samples from children and adults with asthma and/or atopic dermatitis supplied by the Core for human subjects and data analysis (Core B). Sharing samples and overlapping scientific goals among projects create a synergistic program that can be coordinated by a common Administrative Core (Core A). Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in cell and mouse models and translates findings from these models to studies of humans with asthma and/or allergy. In each project, we aim to validate a clinically useful biomarker of the disease process and lay the groundwork for the future development of biological and/or small molecular weight compounds that might influence the process as a therapeutic strategy.

Public Health Relevance

Asthma and allergic diseases are among the most common types of human illness, but we still have an incomplete understanding of what causes these diseases and therefore have no means to specifically diagnose and prevent this type of disease. Here we aim directly at this issue by pursuing newly identified molecular defects in the barrier cells of the airway and the skin that may lead to asthma and allergic disease. As we define and validate these new cellular and molecular defects, we will also develop the means to monitor and correct them and thereby prevent this type of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070489-08
Application #
8508642
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Minnicozzi, Michael
Project Start
2006-07-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$1,473,389
Indirect Cost
$502,374
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Olias, Philipp; Etheridge, Ronald D; Zhang, Yong et al. (2016) Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression. Cell Host Microbe 20:72-82
Lu, Qun; Yokoyama, Christine C; Williams, Jesse W et al. (2016) Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Cell Host Microbe 19:102-13
Dickinson, John D; Alevy, Yael; Malvin, Nicole P et al. (2016) IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12:397-409
Kitcharoensakkul, Maleewan; Bacharier, Leonard B; Yin-Declue, Huiqing et al. (2016) Temporal biological variability in dendritic cells and regulatory T cells in peripheral blood of healthy adults. J Immunol Methods 431:63-5
Xu, Amy Z; Tripathi, Shivani V; Kau, Andrew L et al. (2016) Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus. J Am Acad Dermatol 74:1017-20
Zhang, Yong; Mao, Dailing; Roswit, William T et al. (2015) PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. Nat Immunol 16:1215-27
Morales, David J; Monte, Kristen; Sun, Lulu et al. (2015) Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice. J Virol 89:337-49
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Barrow, Alexander D; Palarasah, Yaseelan; Bugatti, Mattia et al. (2015) OSCAR is a receptor for surfactant protein D that activates TNF-α release from human CCR2+ inflammatory monocytes. J Immunol 194:3317-26
Sheshadri, Ajay; Rodriguez, Alfonso; Chen, Ryan et al. (2015) Effect of Reducing Field of View on Multidetector Quantitative Computed Tomography Parameters of Airway Wall Thickness in Asthma. J Comput Assist Tomogr 39:584-90

Showing the most recent 10 out of 64 publications