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
Bazhanov, Nikolay; Escaffre, Olivier; Freiberg, Alexander N et al. (2017) Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses. Sci Rep 7:41029
Tian, Bing; Patrikeev, Igor; Ochoa, Lorenzo et al. (2017) NF-?B Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol 56:506-520
Zhang, Yueqing; Sun, Hong; Zhang, Jing et al. (2017) Quantitative Assessment of the Effects of Trypsin Digestion Methods on Affinity Purification-Mass Spectrometry-based Protein-Protein Interaction Analysis. J Proteome Res 16:3068-3082
Agod, Zsofia; Fekete, T√ľnde; Budai, Marietta M et al. (2017) Regulation of type I interferon responses by mitochondria-derived reactive oxygen species in plasmacytoid dendritic cells. Redox Biol 13:633-645
Zhao, Yingxin; Jamaluddin, Mohammad; Zhang, Yueqing et al. (2017) Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus-Induced Lower Respiratory Tract Infections. J Immunol 198:3345-3364
Komaravelli, Narayana; Ansar, Maria; Garofalo, Roberto P et al. (2017) Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway. Free Radic Biol Med 113:494-504
German, Peter; Saenz, David; Szaniszlo, Peter et al. (2017) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev 161:51-65
Tian, Bing; Yang, Jun; Zhao, Yingxin et al. (2017) BRD4 Couples NF-?B/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection. J Virol 91:
Ke, Yueshuang; Han, Yanlong; Guo, Xiaolan et al. (2017) PARP1 promotes gene expression at the post-transcriptiona level by modulating the RNA-binding protein HuR. Nat Commun 8:14632
Bazhanov, Nikolay; Ansar, Maria; Ivanciuc, Teodora et al. (2017) Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses. Am J Respir Cell Mol Biol 57:403-410

Showing the most recent 10 out of 145 publications