Exposure to pollens is one of the most common causes of respiratory allergies such as allergic rhinitis and allergic asthma woridwide. We have previously shown that pollens contain an enzyme called NADPH oxidase (pollen-NOX), and that this enzyme is critical for the induction of allergic inflammation. However, very little is known about the molecular mechanism by which these oxidases induce allergic diseases. The goal of this project is to address this critical gap in knowledge about how pollen-NOX induces allergic inflammation. The ain/vay epithelium is the first line of defense against the harmful effects of pollens. Epithelial and intraepithelial dendritic (DCs) cells are two types of cells in the airway epithelium that are the key first responder cells to inhaled pollen allergens. We propose that one of the eariiest events when pollens land on the airway epithelium is that pollen-NOX binds to a receptor on the surface of DCs called Toll-like receptor (TLR4). This cell-surface receptor is best known for its ability to bind to a bacterial product called LPS, but its ability to bind pollen-NOX has not been described. This binding initiates oxidative stress in the DCs that is sufficiently severe to damage DNA, the cells'genetic material. This damaged DNA is repaired by a DNA repair enzyme called OGGI, and 8-oxoG- the damaged base in the DNA, is released. OGGI and 8- oxoG then form a signaling complex in DCs called OGGI-guanine nucleotide exchange factor, or OGG1?^'^. This induces a signaling cascade that activates DCs and promotes allergic inflammation. This model will be tested in three Specific Aims.
In Aim 1 a cell line called 293 and mouse DCs will be used to test how pollen- NOX binds to TLR4, and determine the importance of this binding in the activation of DCs.
Aim 2 will test whether DNA damage and repair induced by pollen-NOX is crucial for activating a signaling cascade that induces allergic lung inflammation in mice.
Aim 3 will test the human relevance of the observations made in cell lines and mice in Aims 1 and 2. We will determine whether binding of pollen-NOX to TLR4 activates DNA damage/repair-mediated signaling pathways in DCs from healthy human subjects and those with allergic rhinitis. We will also perform nasal challenge with pollen extract to healthy subjects and subjects with allergic rhinitis, and determine if this challenge induces DNA damage and repair in the nose. Achieving these Aims should identify novel molecular pathways utilized by pollen NADPH oxidases to activate DCs and induce allergic inflammation in humans, and so identify novel molecular targets for new treatments of allergic rhinitis and allergic asthma.

Public Health Relevance

Exposure to pollens is one of the most common causes of respiratory allergies woridwide. The objective of this project to elucidate the key molecular signaling pathways that mediate pollen-induced allergic inflammation. This critically important knowledge should allow us ultimately to develop inhibitors of these pathways that could provide a novel approach to preventing pollen exposure-induced symptoms and morbidity in patients with allergic rhinitis and asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI062885-06A1
Application #
8465467
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$302,195
Indirect Cost
$104,195
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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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:
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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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