Prostacyclin (PGI2), thromboxane A2 (TXA2) and prostaglandins, notably E2 (PGE2) play important roles in mediating and controlling normal and diseased arterial homeostasis. Biosynthesis of PGI2 and TXA2 is catalyzed by a series of enzymes acting sequentially: phospholipase A2, prostaglandin H synthase (PGHS) and prostacyclin synthase (PGIS) or thromboxane synthase (TXAS). During the previous and current funding periods, we have made important contributions in cloning PGIS, TXAS, characterizing of PGHS-1 and PGHS-2 gene transcription and kinetics of PGI2 and TXA2 biosynthesis. Biosynthesis of PGI2 and TXA2 is regulated not only by the expression of these enzymes but also by their subcellular localization and compartmentalization. The overall objective of this project is to elucidate the mechanisms by which the biosynthesis of these vasoactive prostanoids is regulated and to develop new therapeutic strategies for gene transfer. We wish to test the following hypotheses: (1) constitutively augmented and preferential synthesis of PGI2; and (3) co-localization and geographical coupling of PGHS-1 or -2 with PGIS and TXAS influences PGI2 and TXA2 biosynthesis. To test these inter-related hypotheses, we propose the following four specific aims: (1) characterization of transcriptional activation of PGHS-1 gene; (2) regulation of PGIS expression in human endothelial cells; (3) functional linkage of over-expressed PGIS to isoforms of PGHS in prostacyclin synthesis; and (4) colocalization and geographical coupling of PGIS or TXAS with PGHS-1 or PGHS-2. Results from these experiments will provide new fundamental knowledge on prostanoid biosynthesis and will have valuable impact on developing new strategies for gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS023327-16
Application #
6423097
Study Section
Project Start
2001-02-01
Project End
2002-01-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
16
Fiscal Year
2001
Total Cost
$207,281
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77225
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