Project 3 (Boldogh, I)
Istvan Boldogh, PhD
Professor, Dept. Microbiology and Immunology
3.142 Medical Research Building
Department of Microbiology and Immunology
301 University Blvd.
Galveston, TX 77555-1070
Dr. Boldogh's bio...
Lung inflammation and associated diseases are widespread, affecting nearly a billion people worldwide. In the US alone there are ~20 million outpatient visits, two million emergency room visits, and more than 500,000 hospitalizations yearly for the management of inflammatory lung disease, posing a substantial burden on individuals, families, health-care systems and the entire society. Although there have been significant advances in preventing/ameliorating lung inflammation and disease syndromes, the treatment regimens (e.g., steroids, antioxidants) available today are mostly for the symptoms.
The etiology of inflammatory lung diseases is diverse (e.g., environmental exposures, viral and bacterial infections, trauma, allergens, etc). All first affect the airway epithelium, initiating (and then maintaining) CC and CXCL chemokine expression, and causing alterations to molecules expressed at the epithelial cell surface that are important for leukocyte recruitment. One of the common primary events associated with pro-inflammatory exposures is reactive oxygen species (ROS)-mediated oxidation of guanine due to its lowest ionizing potential among DNA bases. 8-oxoguanine (8-oxoG) in DNA and inflammatory processes, including pulmonary inflammation in allergy, asthma, obstructive pulmonary lung disease and airway remodeling are inseparably twins, but the etiological link has not been established. To maintain genomic integrity and prevent mutations 8-oxoG is excised from DNA by the 8-oxoG DNA glycosylase (OGG1) during DNA base excision repair (BER) pathway the product of which is 8-oxoG base. OGG1 binds the free 8-oxoG and the OGG1|8-oxoG complex has a guanine nucleotide exchange factor activity (OGG1GEF) that increases levels of activated small Ras GTPases. These novel unexpected observation predict that OGG1-BER, via Ras signaling is linked to an innate immune response.
We therefore propose a novel paradigm in which OGG1, via its 8-oxoG-dependent guanine nucleotide exchange factor activity, is etiologically linked to pro-inflammatory gene expression and innate inflammation. The central model will be tested by testing the following hypotheses that:
This project should be the first to establish that OGG1 plays a key role in inflammation independent of its DNA repair function, and triggers signaling for pro-inflammatory chemokine expression. Completing Aims of this project will identify signaling intermediates involved therein, and lay the foundation for novel therapeutic approaches. For example, drugs that inhibit key signaling molecules, or that transiently diminish OGG1 activity or trap, scavenge, or modify its repair product 8-oxoG, should be beneficial for treating innate inflammatory processes not only in airways, but also in the cardiovascular and central nervous systems, or in obesity-associated inflammatory diseases. Developing such therapeutic interventions is the long-term goal of our research. Moreover, inflammatory processes themselves generate ROS and causes oxidative damage to guanine in DNA, consequently 8-oxoG base excision is continuous, which can maintain OGG1’s GEF activity for sustained inflammatory signaling. Thus our studies are likely to provide the basis for understanding the etiology of chronic inflammatory processes in the lungs, as well as other organ systems.
- inflammatory cell accumulation is dependent on OGG1-mediated repair of the DNA lesion 8-oxoG in the airway epithelium;
- OGG|1GEF-induces type-specific activation Ras family members
- K-Ras-induced signaling is required for transcription from pro-inflammatory genes and innate immune response.
- Hajas, G. A. Bacsi, ML. Hegde, TK .Hazra, S. Sur, Z. Radak, X. Ba, and I. Boldogh 8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular responses via the activation of the small GTPase Rac1. Free Radical Biology and Medicine, 61: 384–394, 2013; PMID: 23612479
- Bacsi, A. L. Aguilera-Agurre, ML. Hegde, TK .Hazra, S. Sur, Z. Radak, X. Ba, and I. Boldogh Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation. DNA Repair (Amsterdam) 12(1):18-26, 2013; PMID: 23127499
- Yadav UC, Naura AS, Aguilera-Aguirre L, Boldogh I, Boulares HA, Calhoun WJ, Ramana KV, Srivastava SK. Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3ß Pathway in Mice. PLoS One, 8(2):e57442, 2013 PMID: 23460857; PMCID: PMC3584054
- Boldogh, I., Hajas, G., L. Aguilera-Aguirre, ML. Hegde, Z. Radak, A Bacsi, S. Sur, TK. Hazra, and S. Mitra. Activation of Ras Signaling by 8-oxoguanine DNA Glycosylase Bound to Its Excision Product 8-oxoguanine. J Biol Chem. 287: 20769–20773, 2012; PMID: 22568941; PMCID: PMC3375501
- Hajas, G. A Bacsi, P. German, Z. Radak, TK. Hazra, and I. Boldogh Biochemical identification of a hydroperoxide derivative of the free 8-oxo-7,8-dihydroguanine base. Free Radical Biology and Medicine, 52(4):749-56, 2012 PMID: 22198182; PMCID: PMC3267897
- Hegde ML, Banerjee S, Hegde PM, Bellot LJ, Hazra TK, Boldogh I, Mitra S. Enhancement of NEIL1 Protein-initiated Oxidized DNA Base Excision Repair by Heterogeneous Nuclear Ribonucleoprotein U (hnRNP-U) via Direct Interaction. J Biol Chem. 287(41):34202-11, 2012; PMID: 22902625; PMCID: PMC3464528
- Pazmandi K, Magyarics Z, Boldogh I, Csillag A, Rajnavolgyi E, Bacsi A. Modulatory effects of low-dose hydrogen peroxide on the function of human plasmacytoid dendritic cells. Free Radical Biology and Medicine 52(3):635-645, 2012, PMID: 22178414
- Pazmandi, K., BV. Kumar, K. Szabo, I Boldogh, A. Szoor, G. Vereb, A. Veres, A. Lanyi, E. Rajnavolgyi, A. Bacsi. Reactive oxygen species generated by NAD(P)H oxidases in ragweed subpollen particles activate human monocyte-derived dendritic cells PLOS One 7(12):e52085; 2012 PMID: 23251688; PMCID: PMC3522620
- Mandal SM, Hegde ML, Chatterjee A, Hegde PM, Szczesny B, Banerjee D, Boldogh I, Gao R, Falkenberg M, Gustafsson CM, Sarkar PS, Hazra TK. Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3'-phosphatase in maintenance of mitochondrial genome. J Biol Chem. 287(4): 2819-29, 2012. PMID: 22130663; PMCID: PMC3268439
- Murai, H., Choudhury, B, Qi, H., Wild, J. Dharajiya, N., Vaidya, S., Kalita, A., Bacsi, A, Corry, D., Kurosky, A, Brasier, A, Boldogh, I., and Sur, S. Alternaria-induced release of IL-18 from damaged airway epithelial cells: An NF-kB dependent mechanism of Th2 differentiation. PloS ONE, 2012;7(2):e30280 2012; PMID: 22347372; PMCID: PMC3274547