PPARg in trophoblast and placental development

PPARg 在滋养层和胎盘发育中的作用

基本信息

批准号：
7209050
负责人：
David S Milstone
金额：
$ 29.53万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2009-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209050
关键词：
2,4-thiazolidinedione Adoptive Transfer Adult Affect Agonist Animals Blood Vessels Cells Chimera organism Chorion Complex Conceptus Cultured Cells Disease Embryo Embryonic Development Endothelium Energy Metabolism Failure Fetal Tissues Future Gene Expression Gene Silencing Gene Targeting Genes Genetic Genetically Engineered Mouse Glucose Goals Human Labyrinth Letters Ligands Link Lipids Localized Mediating Molecular Morphogenesis Morula Mothers Mus Mutation PPAR gamma Patient currently pregnant Patients Pattern Peroxisome Proliferator-Activated Receptors Phenotype Placenta Placentation Population Pregnancy Principal Investigator Process Reagent Retinal Cone Role Signal Transduction Site Stem cells Testing Therapeutic Thiazolidinediones Tissues Transgenic Mice Vascular Endothelium activating transcription factor allantois cell type embryonic stem cell fetal gene function programs research study trophoblast

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：胎盘涉及支持胚胎发育的母体和胎儿组织之间的复杂相互作用。基因工程小鼠已经确定了许多调节该过程的基因。特别是，过氧化物酶体增殖物激活受体伽马（PPARGAMMA）的遗传缺乏导致中间造成胎盘衰竭和胚胎致死性。胎儿和母体ppargamma在胎盘期间进行配合，在分支形态发生和迷宫成熟的部位促进绒毛膜中的局部GCM1表达。因此，这种配体激活的转录因子是成年人的葡萄糖，脂质和能量代谢的中心调节剂，还将调节滋养细胞/决结型形态发生的胎儿和母体信号与胎儿基因表达的模式联系起来，对胎盘表达的模式和胎盘表达的模式。但是，几乎没有关于介导ppargamma功能的细胞或分子机制知之甚少。该项目的目的是确定胎盘活性的特定胎儿和母体组织，并确定这些组织如何相互作用。将使用独特的，最近开发的动物和细胞培养试剂：通过基因靶向在全球或有条件缺乏PPARGAMMA的小鼠，胚胎干细胞和带有Ppargamma突变的滋养细胞干细胞。 AIM 1将检验以下假设：母体和胎儿PPARGAMMA合作实现胎盘成功，以使母体ppargamma的药理激活可以挽救ppargamma - / - 胎盘衰竭。母体Ppargamma在GCM1定位，迷宫成熟和胎盘中的作用将被确定，因为药理学激活对PPARGAMMA - / - 胎盘衰竭的影响也将确定。 AIM 2将使用嵌合分析来测试假设，即ppargamma绒毛膜失败是一种间接效应，反映了pPargamma ppargamma的分化和功能的减少，ppargamma ppargamma toss ppargamma toss ppargamma toss and the and andantoiis和lab intantom and andantobers and pargmartial and pargmartial and ppargmartial and ppargmant and ppargmant and ppargmain and ppargmain and pargmain and ppargma and ppargma and ppargma and ppargma and在胎盘中。 AIM 3将使用细胞类型限制的条件基因失活，以研究在骨阶层锥/海绵增生细胞和母体血管内皮菌中表达的ppargamma在GCM1定位，迷宫腹膜置身，腹膜内成熟，腹膜内生存和胚胎生存中的作用。这些研究将提供有关ppargamma在胎盘中作用的重要新机械信息，并可能暗示患者妊娠疾病的未来治疗可能性。