At the initial application five years ago, we had identified the first known prostaglandin (PG) and thromboxane (TX) transporter, which we named """"""""PGT"""""""". With this grant we have found that PGT has a substrate specificity consistent with signal termination via PG uptake, and that it is likely a lactate/PG exchanger, and so is poised energetically for PG uptake. One puzzle, however, has been that PGT protein is expressed strongly in cells that synthesize and release PGs. We now propose a new hypothesis for the cellular control of PG release using PGT: 1) In cells synthesizing PGs, efflux across the plasma membrane occurs by unregulated simple diffusion. However, control of net PG/Tx release is achieved by regulated PGT insertion into the plasma membrane, causing PG reuptake into the cell without intracellular oxidation. 2) In cell types that oxidize PGs, PGT mediates constitutive signal termination via uptake and oxidation. We have evidence for this model: cultured rat renal medullary interstitial cells (RMICs) express PGT. Exposing-RMICs to hypertonic medium causes rapid down-regulation of (PGT-mediated) 3H-PGE2 uptake and a concomitant increase in net PG release.
The Specific Aims of this five-year proposal are to: 1. Develop further the hypothesis that PGT is a PG/lactate exchanger, and define its role in PG release from cells. 2. Define the compartmentation of PG synthetic and degradative pathways in relationship to PGT expression in rat kidney, RMICs, and lung. 3. Characterize PGT isoforms and determine their intracellular expression and transport capacity. 4. Determine the mechanism(s) by which PGT function, PGT protein expression, and PG synthesis are regulated by hypertonicity in RMICs. 5. Examine regulation of PGT expression in the rat kidney in vivo following maneuvers that alter PGE2 production and release.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049688-09
Application #
6635040
Study Section
General Medicine B Study Section (GMB)
Program Officer
Ketchum, Christian J
Project Start
1995-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
9
Fiscal Year
2003
Total Cost
$470,863
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071036636
City
Bronx
State
NY
Country
United States
Zip Code
10461
Jerschow, Elina; Edin, Matthew L; Pelletier, Teresa et al. (2017) Plasma 15-Hydroxyeicosatetraenoic Acid Predicts Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract 5:998-1007.e2
Jerschow, Elina; Ren, Zhen; Hudes, Golda et al. (2016) Utility of low-dose oral aspirin challenges for diagnosis of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 116:321-328.e1
Schuster, Victor L; Chi, Yuling; Lu, Run (2015) The Prostaglandin Transporter: Eicosanoid Reuptake, Control of Signaling, and Development of High-Affinity Inhibitors as Drug Candidates. Trans Am Clin Climatol Assoc 126:248-57
Schuster, Victor L (2015) The ins and outs of prostaglandin E2 in fever. Temperature (Austin) 2:326-7
Chi, Yuling; Jasmin, Jean-Francois; Seki, Yoshinori et al. (2015) Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice. PLoS One 10:e0131735
Liu, Zhongbo; Benard, Outhiriaradjou; Syeda, Mahrukh M et al. (2015) Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats. PLoS One 10:e0133615
Chi, Yuling; Suadicani, Sylvia O; Schuster, Victor L (2014) Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake. Pharmacol Res Perspect 2:e00051
Lim, Jihyeon; Liu, Zhongbo; Apontes, Pasha et al. (2014) Dual mode action of mangiferin in mouse liver under high fat diet. PLoS One 9:e90137
Chi, Yuling; Min, Jaeki; Jasmin, Jean-Francois et al. (2011) Development of a high-affinity inhibitor of the prostaglandin transporter. J Pharmacol Exp Ther 339:633-41
Chi, Yuling; Schuster, Victor L (2010) The prostaglandin transporter PGT transports PGH(2). Biochem Biophys Res Commun 395:168-72

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