The role of the P450 arachidonic acid (AA) monooxygenase as a major pathway for the metabolism of endogenous AA is now well established, as is the functional relevance of its products and of the enzymes responsible for their biosynthesis. Studies with purified proteins, genetic models of hypertension, or mice carrying disrupted P450 genes have identified members of the CYP2C and CYP4A gene subfamily of P450s as the predominant, and functionally relevant AA epoxygenase and omega hydroxylases in the rat, mouse, and human kidney, respectively. Synthetic chemistry, protein chemistry, and recombinant DNA techniques provide now efficient and routine access to most P450 eicosanoids, specific inhibitors, EET and HETE analogs, antagonists and agonist, purified P450 isoforms, P450 antibodies, cDNAs, as well as plasmid and viral vectors coding for CYP2C AA epoxygenase and CYP 4A omega-hydroxylases. In support of projects 1- 5 and, to optimize productive interactions and resources utilization. Core B will continue to apply established methods of eicosanoid extraction, purification, HPLC analysis, UPLC/MS/MS characterization, protein purification, and recombinant DNA manipulation, for: a) the detection and quantification of eicosanoids in biological samples, b) the biochemical characterization of metabolites generated by cellular, subcellular, or purified protein incubates, c) the storage, purification, and documentation of synthetic standards, specific inhibitors, agonist, and antagonists, d) the storage and documentation of immunospecific probes, e) the partial purification of recombinant enzymes, and f) the amplification, purification and documentation of cDNAs probes. The centralization of these routine tasks in Core B eliminates unnecessary and costly duplications, improves reproducibility, and provide projects 1-5 with efficient and timely access to synthetic standards, biospecific probes and state of the art bioanalytical techniques.

Public Health Relevance

Core B serves important roles in the optimization of resources, as well as a vehicle for the productive exchange of ideas and experiences. As the depository of methods and experimental tools, the Core plays an important function in facilitating interactions and promoting effort coordination among the Program Project scientists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK038226-26
Application #
8379577
Study Section
Special Emphasis Panel (ZDK1-GRB-S)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
26
Fiscal Year
2012
Total Cost
$204,061
Indirect Cost
$73,141
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
Paudyal, Mahesh P; Adebesin, Adeniyi Michael; Burt, Scott R et al. (2016) Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353:1144-7
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
Capdevila, Jorge H; Wang, Wenhui; Falck, John R (2015) Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance. Prostaglandins Other Lipid Mediat 120:40-9

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