Preeclampsia is hypertension, proteinuria and edema that develops in the second half of human gestation. Also called toxemia, the disease affects 7% of pregnancies, with a prevalence as high as 20% in minority and indigent populations. Preeclampsia is a major contributor to low birthweight babies, resulting both from intrauterine growth retardation and necessary preterm delivery. The poor outcomes for many of these pregnancies create a burden to society: Increased social resources are needed to optimize development of the affected children and millions of dollars are required to treat the medical complications the children experience. Placental tissue is a prerequisite for the development of preeclampsia. The long term goal of this research is to determine how the placenta predisposes women to this disease. Placental villi from preeclamptic pregnancies produce more thromboxane and less prostacyclin compared to those of normal women. Many sequellae of preeclampsia can be explained by an imbalance of the platelet-aggregating and vasoconstricting actions of excess thromboxane, and the preeclampsia prophylaxis and treatment of intrauterine fetal growth retardation has focused attention on the role eicosanoids, such as thromboxane and prostacyclin, may play in disease pathophysiology, Aspirin inhibits the cyclooxygenase activity of the enzyme prostaglandin endoperoxide synthase (PGS) the first committed step in prostanoic formation. Both eicosanoids are biologically active end products formed by PGS action on arachidonic acid. An important component of the human placenta, villous trophoblast, is used to establish primary cultures of cells characterized to differentiate in vitro. The transcription, translation, and activity of trophoblast PGS expression is studied using Northern blot analysis of mRNA from both the constitutive and inducible PGS genes, immunoprecipitation and Western blot analysis of PGS turnover, and radioimmunoassays of two biologically active end products of PGS activity, thromboxane and prostaglandin E. High performance liquid chromatography is used to analyze media for non-prostanoic products formed by a PGS-catalyzed reaction in aspirin treated trophoblast.
The Specific Aims address: 1) whether PGS is regulated at the transcriptional, transnational, or activity level during in vitro differentiation of villous trophoblast; 2) how a fibrin matrix, platelet- derived growth factor, and aspirin modify this regulation; and 3) whether trophoblast regulation of PGS expression differs in preeclampsia. These studies answer key questions in our goal to design better therapies for the prophylaxis and treatment of this unique human disease.
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