# Linkage of the oxidant induced OGG1-DNA complex to airway inflammation and remodeling

> **NIH NIH P01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $474,000

## Abstract

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections (LRTIs) in children
worldwide. RSV infection rapidly generates reactive oxygen species (ROS) that produce oxidative DNA
damage, with 8-oxoguanine (oxoG) being one of the most abundant. OxoG is repaired by the 8-oxoguanine
DNA glycosylase1 (OGG1)-initiated DNA base excision repair pathway (BER). We have documented that ROS
transiently inactivates OGG1 enzymatic activity, leading to formation of an OGG1-DNA complex in inducible
gene promoters and in close proximity to NFκB-binding motifs. We have also demonstrated that: 1) OGG1-
DNA complex at oxoG increases NFκB binding in vitro; and 2) OGG1 depletion or inhibition of OGG1 substrate
binding by highly selective small molecules result in decrease NFκB-dependent gene expression in vivo. These
data indicate that the OGG1-oxoG complex plays a key role in the innate immune response (IIR). As such, we
recently found that OGG1 is required for RSV-induced expression of innate chemokines, cytokines, and
interleukins constituting the IIR. Related to the overall theme of this P01, we have also shown that repeated
activation of OGG1-dependent innate pathways resulted in modulation of gene networks controlling the actin
cytoskeleton, extracellular matrix, cell adhesion, and cell junction apparatus, resulting in airway remodeling.
Because of the high specificity of OGG1 for oxoG, these results point to a novel paradigm wherein oxoG
functions as an epigenetic element that plays a central role in the regulation of genes that link IIR to airway
remodeling.
The overarching hypothesis of this project is that the RSV-induced oxidation of guanine to oxoG in gene
regulatory regions is an epigenetic modification that links inflammation with airway remodeling via the NFκB
pathway. This hypothesis will be tested in three Specific Aims: 1) RSV-induced pro-inflammatory gene
expression and acute inflammation is dependent on ROS-induced oxidative damage to DNA and OGG1; 2)
The OGG1 DNA complex at·oxoG in the proximal promoter regions of IIR genes serves as a platform for NFκB
binding occupancy in response to RSV infection; 3) The OGG1·DNA complex links chronic oxidative stress
with tissue remodeling in RSV-primed mice in response to allergen challenges.
To achieve these aims, we will utilize mouse models, primary human small airway epithelial cells,
nasopharyngeal cells isolated from RSV-infected infants, and well as state-of-the-art molecular technologies.
Our studies contribute to the understanding of the role of the RSV-ROS-induced OGG1-DNA complex at oxoG
in epigenetic regulation of NFkB-driven expression of IIR and airway remodeling genes in the context of RSV
LRTI. This work will also advance innovative approaches for treatment of LRTI using available small-molecule
inhibitors of OGG1.

## Key facts

- **NIH application ID:** 9974470
- **Project number:** 5P01AI062885-13
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** ISTVAN Steven BOLDOGH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,000
- **Award type:** 5
- **Project period:** 2004-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974470

## Citation

> US National Institutes of Health, RePORTER application 9974470, Linkage of the oxidant induced OGG1-DNA complex to airway inflammation and remodeling (5P01AI062885-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974470. Licensed CC0.

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