Asthma is a chronic relapsing airway disease that represents a major public health problem worldwide. Intermittent exacerbations are provoked by airway mucosal exposure to pro-inflammatory stimuli, with RNA viral infections or inhaled allergens representing the two most common precipitants. This P01 is comprised of 4 synergistic, inter-related projects investigating the overall hypothesis that ROS production by the respiratory mucosa activates the innate immune response {IIR), producing airway inflammation. This mucosal-initiated airway inflammation is modulated by antioxidant proteins and products of endogenous DNA damage-repair. During the past funding period we have made significant advances in understanding how paramyxovirus (Respiratory Syncytial Virus) infections modulate reactive oxygen species (ROS) and innate signaling. In addition, we have defined the mechanisms of pollen (ragweed) intrinsic NADPH-oxidases in modulating ROS and DNA damage-repair pathways in mucosal-resident cells. Our studies will advance the field's understanding of the intricate relationships among ROS, IIR activation and airway hyperresponsiveness. Specifically, we will show how the IIR is activated by ROS to control inflammatory cytokine mRNA elongation by cyclin kinases (P1), how endogenous antioxidant gene responses are modulated by respiratory syncytial virus (P2), how ROS-induced DNA damage/repair pathways affect inflammatory responses (P3), and how ragweed pollen NADPH oxidases bound to the cell membrane via toll-like receptor {TLR) 4 induce intracellular ROS and the DNA damage/repair response (P4 ). These projects will be supported by an Administrative Core (Core A), responsible for scheduling our ongoing meetings, seminars, and interactions with two Advisory groups (Internal and External), and providing biostatistical support to the projects;and a Viral Tissue Culture and Immunoassay Core (VTCIC, Core B), an established core responsible for high-quality viral and cell culture preparations, Bio-Plex, lung function and immunoassays;both cores support all four research projects. These projects function within an established collaborative environment demonstrated by over 52 multi-authored publications, with the involvement of 22 trainees in asthma research, and supported by UTMB's Clinical and Translational Sciences Award, and NHLBI-funded Proteomics Center on airway inflammation. Our work will lay the foundation for future studies aimed at translating the findings from this project period into novel treatments for asthma.

Public Health Relevance

Asthma is a significant public health problem affecting millions of Americans, a disease whose symptoms are exacerbated by environmental exposures. Previous work has shown that the tissues lining the airways play an important role in the response to viruses or pollens, producing signals responsible for worsening asthma symptoms. The projects in this program seek to understand how the lung tissues respond to these signals and how to modulate them, with the long-term goal of developing new treatments for airway inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI062885-06A1
Application #
8415271
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Davidson, Wendy F
Project Start
2005-07-01
Project End
2017-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$1,523,273
Indirect Cost
$525,214
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Tian, Bing; Widen, Steven G; Yang, Jun et al. (2018) The NF?B subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells. J Biol Chem 293:16528-16545
Graber, Ted G; Rawls, Brandy L; Tian, Bing et al. (2018) Repetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia. Exp Gerontol 106:88-100
Tian, Bing; Yang, Jun; Zhao, Yingxin et al. (2018) Central Role of the NF-?B Pathway in the Scgb1a1-Expressing Epithelium in Mediating Respiratory Syncytial Virus-Induced Airway Inflammation. J Virol 92:
Tian, Bing; Hosoki, Koa; Liu, Zhiqing et al. (2018) Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. J Allergy Clin Immunol :
Wang, Ruoxi; Hao, Wenjing; Pan, Lang et al. (2018) The roles of base excision repair enzyme OGG1 in gene expression. Cell Mol Life Sci 75:3741-3750
Tian, Bing; Liu, Zhiqing; Yang, Jun et al. (2018) Selective Antagonists of the Bronchiolar Epithelial NF-?B-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23:1138-1151
Ba, Xueqing; Boldogh, Istvan (2018) 8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified base lesions. Redox Biol 14:669-678
Visnes, Torkild; Cázares-Körner, Armando; Hao, Wenjing et al. (2018) Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 362:834-839
Ochoa, Lorenzo F; Kholodnykh, Alexander; Villarreal, Paula et al. (2018) Imaging of Murine Whole Lung Fibrosis by Large Scale 3D Microscopy aided by Tissue Optical Clearing. Sci Rep 8:13348
Liu, Zhiqing; Tian, Bing; Chen, Haiying et al. (2018) Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur J Med Chem 151:450-461

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