The epoxyeicosatrienoic (EETs) and 20-hydroxyeicosatetraenoic (20-HETE) acids, products of thearachidonic acid (AA) epoxygenase and co-hydroxylase are formed in vivo by rodent and human organs and have been identified as regulators of cell growth, vascular tone, and renal transport. There is now growing evidence of a role for these eicosanoids and the enzymes involved in their biosynthesis in the pathophysiology of diseases such as hypertension. Consequently, the long term goals of this Core are to develop and provide the synthefic experimental tools needed for studies of the physiological and pathophysiological relevance of this metabolic pathway. In response to a growing need for analytical, biological, and pharmacological approaches to studies of mechanisms of acfion and in vivo functional roles, the synthetic chemistry core proposes to: a) design EET, 20-HETE, and PPAR(alpha) analogs with modified chemical, metabolic and pharmacological properties suitable for in vivo applications, b) prepare stable isotope labeled and unlabeled eicosanoids, standards, analogs, and inhibitors in sufficient quantities to support the activities of the PPG laboratories, including in vivo experiments, and c) to provide for the storage, quality assurance, packaging, and distribution of eicosanoids, inhibitors, analogs, standards, and reagents to PPG and other laboratories. Chemical synthesis will be adapted from the literature procedures, or patterned on synthetic routes developed by Core C, with the modifications needed to accommodate increases in scale, or to allow for the incorporation of labeled atoms. Analyfical techniques such as liquid chromatography, mass spectrometry, and NMR will be used to ensure product identity, purity, and isotopic composition. P450 isoform specific inhibitors will be developed and characterized in collaborafion with Project 1, while the biological properties of eicosanoid analogs/agonists/antagonists will be characterized in conjunction with Projects 2-4. Finally, Core C will collaborate with Project 1 in the development of streamlined procedures for the extraction, analysis, and quantification of P450 eicosanoids in human plasma and urine. In light of the limited availability of P450 eicosanoids, analogs and selective inhibitors, the synthefic and analytical resources of Core C are an important component of the PPG research efforts to define the role of P450 In renal function.

Public Health Relevance

As a centralized facility for the development and synthesis of the chemical tools needed for mechanistic studies of the physiological roles and pathophysiological relevance of the renal AA monooxygenase pathway. Core C plays an important role in optimizing the utilization of funds and resources, and in maximizing overall productivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK038226-27
Application #
8521254
Study Section
Special Emphasis Panel (ZDK1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$119,923
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Savas, Ãœzen; Wei, Shouzou; Hsu, Mei-Hui et al. (2016) 20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR. J Biol Chem 291:16904-19
Hye Khan, Md Abdul; Fish, Brian; Wahl, Geneva et al. (2016) Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. Clin Sci (Lond) 130:587-99
Chiba, Takuto; Skrypnyk, Nataliya I; Skvarca, Lauren Brilli et al. (2016) Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. J Am Soc Nephrol 27:495-508
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Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A et al. (2016) p66Shc regulates renal vascular tone in hypertension-induced nephropathy. J Clin Invest 126:2533-46
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Luther, James M; Brown, Nancy J (2016) Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat 125:2-7
Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65
Garcia, Victor; Joseph, Gregory; Shkolnik, Brian et al. (2015) Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 309:R71-8
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