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)
Type
Research Program Projects (P01)
Project #
5P01GM015431-47
Application #
8690871
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
47
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
Simpson, Scott A; Zaccagni, Hayden; Bichell, David P et al. (2014) Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. Pediatr Crit Care Med 15:503-10
Shonesy, Brian C; Bluett, Rebecca J; Ramikie, Teniel S et al. (2014) Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Cell Rep 9:1644-53
Wu, Jing; Thabet, Salim R; Kirabo, Annet et al. (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616-25
Xu, Shu; Hermanson, Daniel J; Banerjee, Surajit et al. (2014) Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding Network. J Biol Chem 289:6799-808
Neau, David B; Bender, Gunes; Boeglin, William E et al. (2014) Crystal structure of a lipoxygenase in complex with substrate: the arachidonic acid-binding site of 8R-lipoxygenase. J Biol Chem 289:31905-13
Shuck, Sarah C; Wauchope, Orrette R; Rose, Kristie L et al. (2014) Protein modification by adenine propenal. Chem Res Toxicol 27:1732-42
Hermanson, Daniel J; Gamble-George, Joyonna C; Marnett, Lawrence J et al. (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358-67
Dikalov, Sergey I; Nazarewicz, Rafal R; Bikineyeva, Alfiya et al. (2014) Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal 20:281-94
Kirabo, Annet; Fontana, Vanessa; de Faria, Ana P C et al. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 124:4642-56
Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15

Showing the most recent 10 out of 31 publications