Project 1: Epigenetic Regulation of Placental and Fetal Gene Expression in Human Pregnancy

项目1：人类妊娠中胎盘和胎儿基因表达的表观遗传调控

• 批准号: 10372961
• 负责人: CHRISTOS COUTIFARIS
• 金额: $ 47.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372961
• 关键词: Abnormal placentation; Affect; Assisted Reproductive Technology; Biopsy; Birth; Birth Weight; Blood Vessels; Cardiovascular Diseases; Cells; Childhood; Clinical; Conceptions; DNA Methylation; DNA methylation profiling; Development; Diabetes Mellitus; Disease; Embryo; Embryo Transfer; Embryonic Development; Endometrial; Endometrium; Endothelial Cells; Environment; Epigenetic Process; Exhibits; Fetal Growth; Fetus; Freezing; Gene Abnormality; Gene Expression; Genes; Gonadotropins; Growth; Health; Hormonal; Human; In Vitro; Incidence; Individual; Laboratories; Lead; Life; Methylation; Molecular; Natural regeneration; Obesity; Outcome; Pathway interactions; Patients; Perfusion; Phenotype; Physiological; Placenta; Placentation; Pregnancy; Protocols documentation; Reproduction; Running; Site; Time; Tissues; Treatment Factor; Umbilical Cord Blood; Woman; adverse outcome; embryo cryopreservation; embryo culture; embryo tissue; epigenetic regulation; fetal; fetal blood; genome-wide; implantation; improved; infertility treatment; mouse model; natural Blastocyst Implantation; offspring; perinatal outcomes; prevent; success; trophoblast

Project Summary A fundamental question relevant to clinical IVF is whether and how the peri-conceptional milieu affects embryo implantation and placentation and how clinical manipulations of this environment influence perinatal outcomes. Changes in trophoblast differentiation and function, perturbations of placental vascular development and/or sub-optimal endometrial regeneration during clinical or laboratory manipulations such as trophectoderm biopsy could all contribute to abnormal implantation and placentation and lead to an abnormal fetal growth phenotype. We hypothesize that epigenetic changes in specific placental cellular compartments (embryonic or extraembryonic) and/or the endometrium contribute to the significant adverse outcomes associated with IVF and, specifically, following fresh (hyperstimulated) vs. frozen/thawed embryo transfer or natural conception or following trophectoderm biosy. We suggest that these epigenetic alterations lead to abnormal gene expression at critical times during development, implantation and placentation and result in abnormal growth and other complications. In Specific Aim 1A we will identify site- and gene-specific epigenetic differences in placentas, in isolated trophoblasts, placental vasculature and endothelial cells from pregnancies following fresh/hyperstimulated vs. frozen/thawed vs. control pregnancies. In Specific Aim 1C, we will begin exploring whether there is an endometrial contribution to the observed peri-conceptional milieu growth-related differences as well. In Specific Aim 2 we will identify specific epigenetic differences in placentas and in isolated trophoblast cells, placental vasculature and endothelial cells in pregnancies following trophectoderm biopsy. In this "clinical" project, we focus on identifying the epigenetic signature(s) related to abnormal placental function and an abnormal birth weight phenotype. In Specific Aim 3 we will determine whether the epigenetic signature determined at birth persists into childhood and may be associated with long term health consequences such as obesity. This initiative continues to be discovery-driven, has and will continue to inform mechanistic studies for our mouse model (Project 2) and should contribute to our understanding of optimal human embryo development, implantation and placentation.

项目摘要 与临床IVF相关的一个基本问题是， 影响胚胎着床和胎盘形成，以及临床如何操作这种环境， 影响围产期结局。滋养层分化和功能的变化， 胎盘血管发育和/或次优子宫内膜再生在临床或 实验室操作（例如滋养外胚层活检）都可能导致异常着床 和胎盘形成并导致异常胎儿生长表型。我们假设表观遗传 特定胎盘细胞区室（胚胎或胚外）和/或 子宫内膜导致与IVF相关的显著不良结果，具体地说， 在新鲜（超刺激）与冷冻/解冻胚胎移植或自然受孕后或 滋养外胚层生物学我们认为，这些表观遗传改变导致异常的基因表达 在发育、着床和胎盘形成过程中的关键时期，导致异常生长， 其他并发症。在具体目标1A中，我们将确定位点和基因特异性表观遗传差异 在胎盘中，在来自妊娠的分离的滋养层、胎盘脉管系统和内皮细胞中 新鲜/超刺激vs.冷冻/解冻vs.对照妊娠。在具体目标1C中，我们将 开始探索是否有子宫内膜的贡献，观察围概念环境 与增长相关的差异。在具体目标2中，我们将确定特定的表观遗传差异， 胎盘和分离的滋养层细胞，胎盘血管和妊娠内皮细胞 滋养外胚层活检后在这个“临床”项目中，我们专注于识别表观遗传 与异常胎盘功能和异常出生体重表型相关的特征。在 具体目标3我们将确定在出生时确定的表观遗传签名是否持续到出生后。 儿童期，并可能与长期的健康后果，如肥胖有关。这一倡议 仍然是发现驱动的，已经并将继续为我们的小鼠的机制研究提供信息 模型（项目2），并应有助于我们了解最佳的人类胚胎发育， 着床和胎盘形成。