Trophoblast-Guided Uterine Transformation in the Establishment of Pregnancy

项目摘要/摘要 胚胎的滋养层细胞衍生品有助于重建子宫环境，这是一个事件 这是成功怀孕所必需的。老鼠和人类各有一个子宫- 胎盘界面，其特征是滋养层细胞在宫内深度渗透，这有助于 子宫免疫细胞、内皮细胞、平滑肌细胞和基质细胞成分的动态变化。 这一重要的发育过程是由具有侵袭性的特殊滋养层细胞指导的。 具有潜在靶向宫腔内母体细胞的特性。在人类身上，这些 侵袭性滋养细胞被称为绒毛外滋养细胞(EVT)。细胞分化的中断 侵袭性滋养细胞/EVT细胞谱系、宫内滋养层细胞侵袭和/或滋养层细胞定向 子宫细胞调节导致早期妊娠丢失、胎盘功能障碍、妊娠相关疾病、 以及一系列的产后健康问题。该项目的重点是胎盘特异性1(PLAC1)，一种内在的 胎盘形成调节剂。我们的长期目标是阐明控制发展的调控过程 侵袭性滋养细胞/EVT细胞谱系及其在建立子宫-胎盘界面中的作用。在这 项目，我们的努力集中在两个目标上。在目标1中，我们剖析了PLAC1在建立 侵袭性滋养层细胞谱系。在目标2中，我们研究滋养层细胞-子宫细胞串扰和 子宫-胎盘界面的可塑性。实验利用基因操纵的功能丧失大鼠 模型、滋养层干细胞以及转录本和染色质景观的全基因组分析。 该研究项目的实施将有助于阐明控制滋养层细胞引导的分子通路。 子宫环境的改变，将为了解子宫内膜异位症的发病机制提供平台 早期妊娠丢失和胎盘异常导致妊娠障碍。

PROJECT SUMMARY/ABSTRACT Trophoblast cell derivatives of the embryo contribute to restructuring the uterine environment, an event required for the establishment of a successful pregnancy. The rat and human each possess a uterine- placental interface that is characterized by deep intrauterine infiltration of trophoblast cells, which contribute to dynamic changes in uterine immune cell, endothelial cell, smooth muscle cell, and stromal cell constituents. This important developmental process is directed by specialized trophoblast cells possessing invasive properties with the potential of targeting maternal cells within the uterine compartment. In the human, these invasive trophoblast cells are referred to as extravillous trophoblast (EVT). Disruptions in differentiation of the invasive trophoblast/EVT cell lineage, intrauterine trophoblast cell invasion, and/or trophoblast cell-directed uterine cell modulation contribute to early pregnancy loss, placental dysfunction, pregnancy-related diseases, and a range of postnatal health issues. The project focuses on placenta specific 1 (PLAC1), an intrinsic regulator of placentation. Our long-term goal is to elucidate regulatory processes controlling development of the invasive trophoblast/EVT cell lineage and its role in establishing the uterine-placental interface. In this project, our efforts are focused on two aims. In Aim 1, we dissect the actions of PLAC1 in the establishment of the invasive trophoblast cell lineage. In Aim 2 we investigate trophoblast cell-uterine cell crosstalk and plasticity at the uterine-placental interface. Experimentation utilizes genetically manipulated loss-of-function rat models, trophoblast stem cells, and genome-wide analyses of transcriptomes and chromatin landscapes. Execution of this research project will facilitate elucidation of molecular pathways controlling trophoblast-guided transformation of the uterine environment and will create a platform for understanding the pathogenesis of early pregnancy loss and placental anomalies leading to pregnancy disorders.