The Research Center for Pharmacology and Drug Toxicology brings together a group of highly experienced investigators with a shared interest in the role of oxygenation of lipids and oxidative stress in disease pathogenesis as a basis for the identification of new pharmacologic strategies for treatment of human disease. The Center is comprised of five research projects and two cores. The proposed research in Project 1 is an evolution of our previous studies in the Center which elucidated that acetaminophen inhibits hemoprotein redox cycling induced lipid peroxidation. Our new studies will investigate the ability of acetaminophen and related compounds to prevent apoptosis by inhibiting cytochrome c redox cycling induced oxidation of cardiolipin, an essential component of the apoptotic cascade. The proposed research in Project 2 is comprised of two clinical projects. One will evaluate the ability of acetaminophen to inhibit hemoglobin redox cycling induced lipid peroxidation in patients with subarachnoid hemorrhage and the second project will evaluate the ability of acetaminophen to inhibit hemoglobin and myoglobin induced oxidative stress in patients undergoing cardiopulmonary bypass surgery. The proposed research in Project 3 will explore the selective oxygenation of endocannabinoids by cyclooxygenase-2 to form 2-arachidonoylethanolamide and 2-arachidonoylglycerol and their substrate- selective inhibition by low concentrations of non-steroidal anti-inflammatory drugs (NSAIDs). 'The proposed research in Project 4 will explore approaches to therapeutically modulate levels of endothelial cell tetrahydrobiopterin as a means to prevent oxidative stress due to uncoupling of nitric oxide synthase. The proposed research in Project 5 will explore the mechanisms underlying the biosynthesis of leukotriene-A type fatty acid epoxides, which are key intermediates in the formation of pro-inflammatory leukotrienes and eoxins and the pro-resolving lipoxins, resolvins, protectins, and maresins.

Public Health Relevance

It is anticipated that these studies will lead to (a) effective novel pharmacologic approaches to prevent apoptotic death in settings such as myocardial infarction and stroke and hemoprotein mediated oxidative damage in settings of subarachnoid hemorrhage and cardiopulmonary bypass surgery, (b) new insights into some of the unexplained actions of NSAID's, (c) new therapeutic approaches to improve vascular function by enhancing levels of tetrahydrobiopterin and (d) new insights into potential ways to pharmacologically modulate the formation of resolvins, protectins, lipoxins, and maresins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM015431-46
Application #
8489123
Study Section
Special Emphasis Panel (ZGM1-PPBC-6 (CP))
Program Officer
Okita, Richard T
Project Start
1997-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
46
Fiscal Year
2013
Total Cost
$1,847,423
Indirect Cost
$655,109
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Teder, Tarvi; Boeglin, William E; Brash, Alan R (2017) Oxidation of C18 Hydroxy-Polyunsaturated Fatty Acids to Epoxide or Ketone by Catalase-Related Hemoproteins Activated with Iodosylbenzene. Lipids 52:587-597
Teder, Tarvi; Boeglin, William E; Schneider, Claus et al. (2017) A fungal catalase reacts selectively with the 13S fatty acid hydroperoxide products of the adjacent lipoxygenase gene and exhibits 13S-hydroperoxide-dependent peroxidase activity. Biochim Biophys Acta 1862:706-715
Plewes, Katherine; Kingston, Hugh W F; Ghose, Aniruddha et al. (2017) Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. BMC Infect Dis 17:313
Kong, Deping; Li, Juanjuan; Shen, Yujun et al. (2017) Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1. J Pharmacol Exp Ther 360:435-444
Gamble-George, Joyonna Carrie; Baldi, Rita; Halladay, Lindsay et al. (2016) Cyclooxygenase-2 inhibition reduces stress-induced affective pathology. Elife 5:
Adeniji, Adegoke; Uddin, Md Jashim; Zang, Tianzhu et al. (2016) Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. J Med Chem 59:7431-44
Kudalkar, Shalley N; Kingsley, Philip J; Marnett, Lawrence J (2016) Assay of Endocannabinoid Oxidation by Cyclooxygenase-2. Methods Mol Biol 1412:205-15
Wu, Jing; Montaniel, Kim Ramil C; Saleh, Mohamed A et al. (2016) Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension 67:461-8
Harrison, D G; Guzik, Tomasz J (2016) Macrophages come to mind as keys to cognitive decline. J Clin Invest 126:4393-4395
Montaniel, Kim Ramil C; Harrison, David G (2016) Is Hypertension a Bone Marrow Disease? Circulation 134:1369-1372

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