This application addresses the mechanisms by which prostaglandin (PG) signaling is terminated. PCs signal a diverse array of cellular events. This signaling diversity requires that PCs be inactivated quickly and over short distances. Evidence from our laboratory and others indicates that PG inactivation requires two sequential steps: a) carrier-mediated active PG uptake into cells;and b) subsequent intracellular oxidation. Our laboratory identified, and has extensively characterized, the PG uptake carrier """"""""PGT"""""""". Mice in which we have globally disrupted PGT gene expression die on post-natal day 1 from patent ductus arteriosus. In contrast, mice in which we have selectively deleted PGT from the collecting duct excrete dilute urine, have decreased collecting duct aquaporin-2 expression, and excrete more Na+ than controls. These results are consistent with our findings in cultured cells, i.e. that PGT up-regulates cell surface EP4 receptors. Finally, we find that PGT transports prostacyclin (PGI2) and that PGT knockout mice have prolonged bleeding times, consistent with a proposed role of PGT to remove PGI2 from the vascular lumen. We have three Specific Aims: 1. Test the hypothesis that PG uptake by PGT is critical for systemic PGE2 metabolism in vivo. 2. Test the hypothesis that PGT regulates PG signaling in the renal collecting duct (CD). 3. Test the hypothesis that PGT regulates PG receptor signaling in the vasculature. These studies represent a paradign shift in the area of PG signaling and its control. As such, the work offers the potential to open up new approaches to the management of pain, fever, inflammation, hypertension, and a variety of other medical conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Ketchum, Christian J
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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