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 #
5P01AI062885-07
Application #
8534687
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Davidson, Wendy F
Project Start
2005-07-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$1,426,621
Indirect Cost
$493,699
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
Belanger, KarryAnne K; Ameredes, Bill T; Boldogh, Istvan et al. (2016) The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma. Mediators Inflamm 2016:3762561
Hosoki, Koa; Itazawa, Toshiko; Boldogh, Istvan et al. (2016) Neutrophil recruitment by allergens contribute to allergic sensitization and allergic inflammation. Curr Opin Allergy Clin Immunol 16:45-50
Choudhary, Sanjeev; Boldogh, Istvan; Brasier, Allan R (2016) Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity. J Innate Immun 8:143-55
Nicholson, Erin G; Schlegel, Chelsea; Garofalo, Roberto P et al. (2016) Robust Cytokine and Chemokine Response in Nasopharyngeal Secretions: Association With Decreased Severity in Children With Physician Diagnosed Bronchiolitis. J Infect Dis 214:649-55
German, Peter; Saenz, David; Szaniszlo, Peter et al. (2016) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev :
Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R et al. (2016) Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment. Am J Respir Cell Mol Biol 54:81-90
Ivanciuc, Teodora; Sbrana, Elena; Ansar, Maria et al. (2016) Hydrogen Sulfide Is an Antiviral and Antiinflammatory Endogenous Gasotransmitter in the Airways. Role in Respiratory Syncytial Virus Infection. Am J Respir Cell Mol Biol 55:684-696
Bacsi, Attila; Pan, Lang; Ba, Xueqing et al. (2016) Pathophysiology of bronchoconstriction: role of oxidatively damaged DNA repair. Curr Opin Allergy Clin Immunol 16:59-67
Chakraborty, Anirban; Tapryal, Nisha; Venkova, Tatiana et al. (2016) Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes. Nat Commun 7:13049
Hosoki, Koa; Boldogh, Istvan; Aguilera-Aguirre, Leopoldo et al. (2016) Myeloid differentiation protein 2 facilitates pollen- and cat dander-induced innate and allergic airway inflammation. J Allergy Clin Immunol 137:1506-1513.e2

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