Placentation involves complex interactions between maternal and fetal tissues that support embryonic development. Genetically engineered mice have identified many genes that regulate this process. In particular, genetic deficiency of peroxisome proliferator activated receptor gamma (PPARgamma) leads to placental failure and embryonic lethality at midgestation. Fetal and maternal PPARgamma cooperate during placentation, promoting localized gcm1 expression in chorion at sites of branching morphogenesis, and labyrinth maturation. Thus, this ligand-activated transcription factor, a central regulator of glucose, lipid, and energy metabolism in adults, also links fetal and maternal signals regulating trophoblast/decidual morphogenesis with a pattern of fetal gene expression critical for placentation and embryo survival. However, virtually nothing additional is known about cellular or molecular mechanisms mediating PPARgamma functions in placenta. The goal of this project is to identify specific fetal and maternal tissues in which PPARgamma activity is required for placentation, and to determine how these tissues interact. Unique, recently developed animal and cell culture reagents will be used: mice rendered globally or conditionally deficient in PPARgamma by gene targeting, and embryonic stem cells and trophoblast stem cells harboring mutations of PPARgamma.
Aim 1 will test the hypothesis that maternal and fetal PPARgamma cooperate to achieve successful placentation, such that pharmacologic activation of maternal PPARgamma can rescue PPARgamma-/- placental failure. The role of maternal PPARgamma in gcm1 localization, labyrinth maturation, and placentation will be determined as will the effect of pharmacologic activation on PPARgamma-/- placental failure.
Aim 2 will use chimera analysis to test the hypotheses that labyrinth failure by PPARgamma chorion is an indirect effect, reflecting diminished ectoplacental cone/spongiotrophoblast differentiation and function, that PPARgamma regulates endothelial vascular endothelial differentiation in allantois and labyrinth, and that PPARgamma regulates other trophoblast genes functioning later in placentation.
Aim 3 will use cell-type restricted conditional gene inactivation to investigate the role of PPARgamma expressed in ectoplacental cone/spongiotrophoblast and maternal vascular endothetium in gcm1 localization, labyrinth maturation, placentation, and embryo survival. These studies will provide significant new mechanistic information about the role of PPARgamma in placentation, and may suggest future therapeutic possibilities for gestational disease in patients.
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