This project will evaluate the properties of a novel glutathione peroxidase enzyme that is considerably enriched in lungs. This recently described protein (called 1-cys Peroxiredoxin or Peroxiredoxin 6, Prdx 6) represents the only non-selenium glutathione peroxidase of relatively high specific activity. An important characteristic in the spectrum activity for this enzyme is its ability, unlike classical glutathione peroxidase, to reduce phospholipid hydroperoxides. During the present grant Support as an R-01, we have demonstrated induction of Prdx 6 during hyperoxic stress and provided evidence that the enzyme protects against oxidant stress in cell culture and whole animal studies. Further, we have developed methods for isolation of Prdx 6 protein from rat and bovine lungs and have established expression systems for generation of active recombinant protein. We postulate that reduction of oxidized membrane phospholipids represents the basis for the anti-oxidant effect of the enzyme.
Specific Aim I will utilize mouse models of altered Prdx 6 expression to continue our studies of the role of Prdx 6 in anti-oxidant defense. One of the models, Prdx 6 knock-out mice, was developed during the present period of grant support. The second Specific Aim will investigate control of Prdx 6 expression with special emphasis on the anti-oxidant response element and Nrf 2.
Specific Aim 3 will evaluate substrate-protein interactions with a special focus on phospholipid binding by the protein as a requirement for the phospholipid hydroperoxide peroxidase activity. These studies will utilize site directed mutagenesis based on deduction from the crystal structure of the enzyme.
Specific Aim 4 will utilize cellular systems for analysis of the role of nGST in activation of Prdx 6 activity. The proposed studies will provide a coordinated effort to investigate the role of this novel anti-oxidant enzyme in lung defense against oxidant stress and will provide new information concerning the biochemical regulation of its enzymatic activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL079063-02
Application #
7312633
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$472,897
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43
Myerson, Jacob W; Anselmo, Aaron C; Liu, Yaling et al. (2016) Non-affinity factors modulating vascular targeting of nano- and microcarriers. Adv Drug Deliv Rev 99:97-112
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Chatterjee, Shampa; Nieman, Gary F; Christie, Jason D et al. (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307:L668-80
Reilly, John P; Bellamy, Scarlett; Shashaty, Michael G S et al. (2014) Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma. Ann Am Thorac Soc 11:728-36
Shashaty, Michael G S; Kalkan, Esra; Bellamy, Scarlett L et al. (2014) Computed tomography-defined abdominal adiposity is associated with acute kidney injury in critically ill trauma patients*. Crit Care Med 42:1619-28
Meyer, Nuala J; Feng, Rui; Li, Mingyao et al. (2013) IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med 187:950-9
Shashaty, Michael G S; Meyer, Nuala J; Localio, A Russell et al. (2012) African American race, obesity, and blood product transfusion are risk factors for acute kidney injury in critically ill trauma patients. J Crit Care 27:496-504

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