Oxidative DNA base damage is linked to inflammatory processes, but there are major shortcomings in understanding their disease etiology despite considerable efforts. The most abundant DNA base lesion, 8- oxoguanine (8-oxoG) is linked to inflammation, various age-associated diseases, and aging processes. It is excised from DNA by the 8-oxoG DNA glycosylase (0GG1) and the DNA base excision repair (BER) pathway. Unexpectedly, supraphysiological 8-oxoG levels in Oggi knockout mice do not show major pathologies;in fact, they have increased resistance to inflammation. An increase in 8-oxoG levels in DNA is the earliest event upon oxidative exposure of airways;however, its role in triggering inflammation is suspected but not understood. We have made unexpected discoveries showing that 1) OGGI depletion from the airway epithelium before oxidative exposure significantly decreased innate inflammatory responses;2) 0GG1 binds its repair product, free 8-oxoG base;3) the OGG1?8-oxoG complex has a guanine nucleotide exchange factor activity that 4) increases levels of activated small Ras GTPases and 5) leads to activation of NF-KB/RelA. Proiect 3 seeks to establish a novel paradigm in which 0GG1-initiated DNA BER is etiologically linked to oxidative stress-induced proinflammatory gene expression and inflammation. This will be done by pursuing three Specific Aims, to:
Aim 1) establish the role of OGGI-initiated DNA BER in inflammatory cell accumulation after oxidative stress exposure in the lungs;
Aim 2) elucidate the role of OGGI in activation of the NF-kB/RelA pathway;
and Aim 3) identify the OGGI-induced signaling pathway(s) that trigger proinflammatory gene expression and inflammation. Our hypotheses will be tested using knock-out/transgenic mice and cell lines and such state-of-the-art molecular techniques as siRNA-based ablation of gene expression, real-time PCR, confocal microscopy, and cytokine/chemokine and RNA arrays. These studies should be the first to establish the role of OGGI and identify its novel signaling pathways that facilitate innate lung inflammation. As repair by 8-oxoG by OGG1 is continuous, the results from these studies may also shed light on understanding chronic inflammation in allergic asthma, chronic obstructive pulmonary disease, airway remodeling and lung malignancies;each poses a significant burden on individuals, families, health care systems and the entire society, here in the US and worldwide. Our compelling preliminary data, excellent collaborations in this POI, and UTMB's outstanding resources and intellectual environment make us uniquely suited to do this work.
Lung inflammatory diseases are the fourth leading cause of death, and have a devastating impact on individuals, families and health care systems;their treatments exceeds $42 billion annually in the US. Our goal is to understand their fundamental mechanisms and identify new drug targets, and so lay the foundation for novel treatment approaches. For example, drugs that modulate the activity of OGGI or that scavenge/ modify its byproducts should be excellent candidates to prevent or treat lung inflammation and disease.
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