This project will evaluate the properties of a novel glutathione peroxidase enzyme that is considerably enriched in lungs and plays an important role in lung antioxidant defense and lung surfactant metabolism. This recently described protein called peroxiredoxin 6 (Prdx6 or 1-cys Peroxiredoxin) represents the only non-selenium glutathione peroxidase of relatively high specific activity. An important characteristic in the activity spectrum for this enzyme is its ability, unlike classical glutathione peroxidase, to reduce phospholipid hydroperoxides as, for example, peroxidation of membrane phospholipids during oxidant stress. During the past 4 years of support as a component project of a P-01 grant, we have demonstrated that Prdx6 plays a seminal role in defense of lungs against oxidant stress (hyperoxia, paraquat), that the promoter of the gene contains an antioxidant response element that is sensitive to the transcription factor Nrf2, and have developed a model based on lipid binding studies for the coordination of the peroxidase (Prx) and phospholipase (PLA2) activities of the protein. We are now seeking 5 years of support to extend these studies.
Specific Aim 1 will utilize """"""""knock-in"""""""" technology in the Prdx6 null cells to evaluate the respective contributions of the 2 activities (Prx, PLA2) to antioxidant protection.
This aim will also directly compare the relative roles of Prdx6 and the other major glutathione peroxidase (GPx1) in antioxidant protection.
Specific Aim 2 will study induction of Prdx6 by combined KGF and dexamethasone treatment, which our preliminary data indicate have a synergistic effect on Prdx6 expression.
Specific Aim 3 will continue studies to evaluate structure-function characteristics of the protein with a special focus on phospholipid binding as a requirement for the phospholipid hydroperoxide peroxidase activity and the role of Prdx6 post-translational modifications.
Specific Aim 4 will utilize cellular systems for analysis of the role of pGST in activation of Prdx6 activity. The proposed studies will provide a coordinated effort to investigate the role of this novel antioxidant enzyme in lung defense against oxidant stress and will provide new information concerning the biochemical regulation of its enzymatic activity. This information could lead to new approaches to increasing the ability of the lung to tolerate oxidant stress.

Public Health Relevance

We have characterized a novel enzyme which has two important activities that serve to protect the lungs against oxidant stress and also regulate metabolism of the lung surfactant. Our goals for the program are to evaluate the two activities of the enzyme to determine their relative importance in antioxidant defense, to investigate how the structure of the protein influences activity, and to determine methods for increasing the expression of the protein in lung cells. Understanding this role of peroxiredoxin 6 will facilitate this as a new target for increasing the ability of the lung cells to survive oxidant stress.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
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University of Pennsylvania
Schools of Medicine
United States
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Fisher, Aron B (2018) The phospholipase A2 activity of peroxiredoxin 6. J Lipid Res 59:1132-1147
Fisher, Aron B; Vasquez-Medina, Jose P; Dodia, Chandra et al. (2018) Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of peroxidized cell membranes. Redox Biol 14:41-46
Fisher, Aron B (2017) Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling. Arch Biochem Biophys 617:68-83
Moawad, Adel R; Fernandez, Maria C; Scarlata, Eleonora et al. (2017) Deficiency of peroxiredoxin 6 or inhibition of its phospholipase A2 activity impair the in vitro sperm fertilizing competence in mice. Sci Rep 7:12994
Fisher, Aron B; Dodia, Chandra; Sorokina, Elena M et al. (2016) A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6. J Lipid Res 57:587-96
Zhou, Suiping; Sorokina, Elena M; Harper, Sandra et al. (2016) Peroxiredoxin 6 homodimerization and heterodimerization with glutathione S-transferase pi are required for its peroxidase but not phospholipase A2 activity. Free Radic Biol Med 94:145-56
Krishnaiah, Saikumari Y; Dodia, Chandra; Sorokina, Elena M et al. (2016) Binding sites for interaction of peroxiredoxin 6 with surfactant protein A. Biochim Biophys Acta 1864:419-25
Vázquez-Medina, José Pablo; Dodia, Chandra; Weng, Liwei et al. (2016) The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages. FASEB J 30:2885-98
Sorokina, Elena M; Dodia, Chandra; Zhou, Suiping et al. (2016) Mutation of Serine 32 to Threonine in Peroxiredoxin 6 Preserves Its Structure and Enzymatic Function but Abolishes Its Trafficking to Lamellar Bodies. J Biol Chem 291:9268-80
Benipal, Bavneet; Feinstein, Sheldon I; Chatterjee, Shampa et al. (2015) Inhibition of the phospholipase A2 activity of peroxiredoxin 6 prevents lung damage with exposure to hyperoxia. Redox Biol 4:321-7

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