The objective of this proposal is to characterize the function of Peroxisome Proliferator-Activated Receptors (PPARs) in normal human pregnancy, and in the metabolic disturbances associated with the pregnancy syndrome, preeclampsia (PE). PE is responsible for 20% of maternal deaths in the U.S. PE occurs suddenly in the late second or third trimester of pregnancy and is characterized by high blood pressure, proteinuria, and generalized edema. The cause of PE remains elusive, and the only effective treatment is immediate delivery of the baby, resulting in high levels of infant morbidity and mortality due to complications of premature birth. Thus, both mother and child suffer serious health risks due to this syndrome. This project will evaluate PPAR regulation of maternal energy metabolism in normal pregnancy, and its possible alteration in PE. Although they are not as widely recognized as the classical triad of PE signs (i.e., hypertension, proteinuria and edema), dyslipidemia, obesity and aberrant glucose tolerance also are common facets of the PE syndrome. PPARs play critical roles in the regulation of lipid and glucose metabolism, and we have demonstrated that circulating PPAR activators increase during the course of normal pregnancy. In Specific Aim 1, we propose to use mass spectrometry, as an adjunct to our existing analyses by HPLC, to identify the PPAR activator(s) present in pregnancy plasma. Ligand binding assays will determine whether the identified compound(s) is a direct high affinity ligand of PPARs. We also will determine which specific PPARs are bound and activated by the circulating compound(s). In Specific Aim 2, we have selected two candidate genes (human placental lactogen [hPL] and vascular endothelial growth factor [VEGF]) that play key roles in placental growth and function. Our preliminary studies indicate that PPARs can regulate both genes and that the expression of both gene products is altered in PE. Using a specific inhibitor of PPARg, differences in expression and secretion of hPL and VEGF, due in whole or in part to PPARg activity, will be quantified. In Specific Aim 3, the frequency of PPAR polymorphisms known to alter PPAR function in vivo will be examined in both normal and PE pregnancy. PCR amplification of regions encoding each specific genetic mutation will be followed by diagnostic restriction enzyme digestion in order to genotype both mothers and babies of normal and PE pregnancies. Single nucleotide polymorphisms in these genes also will be sought. We anticipate that our multi-faceted approach to elucidate the role of PPAR action in normal pregnancy and PE will provide new clues to the underlying pathophysiology, and ultimately, therapy of PE and its clinical complications.

R01HL073469

2003-05-01

2008-04-30