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.

National Institute of Health (NIH)
Research Program Projects (P01)
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Transplantation Biology &Immunology-2 (AITC)
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Davidson, Wendy F
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University of Texas Medical Br Galveston
Internal Medicine/Medicine
Schools of Medicine
United States
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Brasier, Allan R (2014) Application of translational science to the clinical problem of asthma. Preface. Adv Exp Med Biol 795:v - vii
Bertolusso, Roberto; Tian, Bing; Zhao, Yingxin et al. (2014) Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. PLoS One 9:e93396
Luo, Jixian; Hosoki, Koa; Bacsi, Attila et al. (2014) 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and ?-smooth muscle actin polymerization. Free Radic Biol Med 73:430-8
Ba, Xueqing; Aguilera-Aguirre, Leopoldo; Rashid, Qura Tul Ain Nmi et al. (2014) The role of 8-oxoguanine DNA glycosylase-1 in inflammation. Int J Mol Sci 15:16975-97
Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Radak, Zsolt et al. (2014) Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-?B pathway. J Immunol 193:4643-53
Li, Xueling; Zhao, Yingxin; Tian, Bing et al. (2014) Modulation of gene expression regulated by the transcription factor NF-?B/RelA. J Biol Chem 289:11927-44
Ba, Xueqing; Bacsi, Attila; Luo, Jixian et al. (2014) 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. J Immunol 192:2384-94
Fang, Ling; Choudhary, Sanjeev; Zhao, Yingxin et al. (2014) ATM regulates NF-?B-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment. Nucleic Acids Res 42:8416-32
Ijaz, Talha; Pazdrak, Konrad; Kalita, Mridul et al. (2014) Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J 7:13
Kolli, Deepthi; Gupta, Meera R; Sbrana, Elena et al. (2014) Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. Am J Respir Cell Mol Biol 51:502-15

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