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

项目摘要 与临床试管受精相关的一个基本问题是，围产期环境是否以及如何 影响胚胎植入和胎盘形成以及这种环境的临床操作 影响围产期结局。滋养层细胞分化和功能的变化，滋养细胞的扰动 胎盘血管发育和/或子宫内膜再生在临床或 实验室操作，如滋养外胚层活检，都可能导致异常着床 和胎盘形成，并导致胎儿生长表型异常。我们假设表观遗传学 特定胎盘细胞隔室(胚胎或胚胎外)的变化和/或 子宫内膜导致了与试管受精相关的严重不良结局，尤其是， 新鲜(超刺激)与冷冻/解冻胚胎移植或自然受孕或后续 滋养外胚层生物。我们认为这些表观遗传改变会导致基因表达异常。 在发育、植入和胎盘形成的关键时刻，会导致异常生长和 其他并发症。在具体目标1中，我们将确定特定部位和特定基因的表观遗传学差异 在胎盘中，在分离的滋养层细胞、胎盘血管系统和妊娠的内皮细胞中 在新鲜/过度刺激与冷冻/解冻与对照妊娠后。在具体的目标1C中，我们将 开始探索子宫内膜是否对观察到的围产期环境有影响 与增长相关的差异也是如此。在特定目标2中，我们将确定特定的表观遗传学差异 妊娠胎盘及分离的滋养层细胞、胎盘血管和内皮细胞 在滋养外胚层活检后。在这个“临床”项目中，我们专注于识别表观遗传学 签名(S)与胎盘功能异常和出生体重异常表型有关。在……里面 具体目标3我们将确定出生时确定的表观遗传特征是否持续到 儿童时期，并可能与肥胖等长期健康后果有关。这一倡议 继续以发现为驱动力，已经并将继续为我们的老鼠提供机制研究 模型(项目2)，应该有助于我们理解人类胚胎的最佳发育， 植入和胎盘植入。

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.