Trophoblast-Guided Uterine Transformation in the Establishment of Pregnancy

滋养细胞引导子宫转化以建立妊娠

• 批准号: 10446395
• 负责人: MICHAEL J SOARES
• 金额: $ 46.09万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446395
• 关键词: Abruptio Placentae; Cell Communication; Cell Lineage; Cells; Chromatin; Development; Developmental Process; Diagnostic; Disease; Early Diagnosis; Embryo; Endothelial Cells; Environment; Etiology; Event; Failure; Fetal Growth Retardation; Functional disorder; Goals; Health; Human; Immune; Infiltration; Modeling; Molecular; Pathogenesis; Pathway interactions; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Process; Property; Rattus; Research Project Grants; Role; Site; Smooth Muscle Myocytes; Stromal Cells; Therapeutic Intervention; Uterus; early pregnancy loss; genetic manipulation; genome-wide analysis; loss of function; obstetrical syndromes; postnatal; pregnancy disorder; targeted treatment; transcriptome; trophoblast; trophoblast stem cell

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.

项目摘要/摘要 胚胎的滋养细胞细胞衍生物有助于重组子宫环境，这是一个事件 建立成功怀孕所必需的。大鼠和人都有子宫 - 胎盘界面的特征是深层宫内滋养细胞的浸润，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。 这个重要的发展过程由具有侵入性的专业滋养细胞指导 具有靶向子宫室内母体细胞的潜力的特性。在人类中，这些 侵入性滋养细胞细胞称为跨滋养细胞（EVT）。差异化的破坏 侵入性滋养细胞/EVT细胞谱系，宫内滋养细胞侵袭和/或滋养细胞指导 子宫细胞调节导致早期妊娠丧失，胎盘功能障碍，与妊娠相关疾病， 以及一系列产后健康问题。该项目侧重于胎盘特异性1（plac1），一个固有的 胎盘调节器。我们的长期目标是阐明控制开发的监管过程 侵入性滋养细胞/EVT细胞谱系及其在建立子宫局部界面中的作用。在这个 项目，我们的努力集中在两个目标上。在AIM 1中，我们剖析了Plac1在建立中的行动 侵入性滋养细胞细胞谱系。在AIM 2中，我们研究了滋养细胞细胞 - 乌顿细胞串扰和 子宫局部界面的可塑性。实验利用了基因操纵的功能丧失大鼠 转录组和染色质景观的模型，滋养细胞干细胞以及全基因组分析。 该研究项目的执行将有助于阐明控制滋养细胞引导的分子途径 子宫环境的转化，并将创建一个平台来理解 早期妊娠丧失和胎盘异常导致妊娠障碍。