Trophoblast-Uterine Cell Dynamics at the Maternal-Fetal Interface

母胎界面的滋养层-子宫细胞动力学

基本信息

批准号：
10271279
负责人：
MICHAEL J SOARES
金额：
$ 14.73万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10271279
关键词：
Affect Animal Model Biological Assay Cells Chromatin Complex Mixtures Computer Analysis Data Data Set Development Endothelial Cells Endothelium Etiology Exhibits Experimental Models Fetal Growth Retardation Fetus Future Genetic Goals Health Hemochorial Placental Development Human Immune Investigation Maternal-Fetal Exchange Modeling Mus Physiological Placenta Placentation Population Pre-Eclampsia Pregnancy Premature Birth Property Rattus Regulator Genes Research Site Smooth Muscle Myocytes Spiral Artery of the Endometrium Stromal Cells Structure Testing Therapeutic Intervention Transposase Uterus Villous candidate identification cell type early pregnancy loss gain of function genetic manipulation in vivo Model insight loss of function obstetrical syndromes single-cell RNA sequencing success targeted treatment trait transcriptome transcriptomics trophoblast trophoblast stem cell

项目摘要

The maternal-fetal interface is a dynamic site where uterine and placental structures cooperate to promote development of the fetus. The rat, mouse, and human each possess a hemochorial placenta. Trophoblast cells are the parenchymal cells of the placenta and have the capacity to differentiate into specialized cell types, including cells that exhibit invasive properties with the potential to enter the vasculature and restructure uterine spiral arteries. In the human, these invasive trophoblast cells are referred to as extra villous trophoblast cells. Disruptions of trophoblast invasion and trophoblast-directed uterine spiral remodeling are centerpieces of the “Great Obstetrical Syndromes”, including early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth. The hemochorial placenta comes in different forms, which impact the suitability of animal models for investigating trophoblast cell invasion and uterine spiral artery remodeling. In contrast to the mouse, the rat exhibits hemochorial placentation with deep intrauterine trophoblast cell invasion, a feature also observed in human placentation. The rat can be effectively used to test the physiological relevance of putative regulators of invasive/extra villous trophoblast cell development. The long-term goal of our research is to identify conserved regulators of invasive/extra villous trophoblast cell development and invasive trophoblast/extra villous trophoblast-guided uterine spiral artery remodeling. We will use single-cell RNA-sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin-sequencing (ATAC-seq) of cell populations isolated from the uterine-placental interface through gestation of the rat. Sequencing data will be interrogated through robust computational analyses and integrated with existing datasets generated for cells within the human uterine-placental interface. This task is best accomplished through the coordinated efforts of experts on rat placentation and computational analysis of the trophoblast transcriptome. The experimentation will provide a robust list of candidate-conserved regulators of invasive trophoblast/extra villous trophoblast cell development and trophoblast-guided uterine spiral artery remodeling for future analysis. Furthermore, we will gain new insights into other essential constituents of the uterine- placental interface, including immune, endothelial, stromal, and smooth muscle cells, which importantly contribute to the health and success of pregnancy. The insights gained from the investigation will fuel future analyses using a pipeline of loss-of-function and gain-of-function approaches in human trophoblast stem cells and genetically manipulated rat models.

母体-胎儿界面是子宫和胎盘结构共同促进胎儿发育的动态部位。大鼠、小鼠和人类均具有血绒质胎盘细胞，是胎盘的实质细胞，具有分化能力。分化成特殊的细胞类型，包括具有侵入性的细胞，具有进入脉管系统并重建子宫螺旋动脉的潜力，在人类中，这些侵入性滋养层细胞被称为。绒毛外滋养层细胞的破坏和滋养层定向的子宫螺旋重塑是“大产科综合征”的核心，包括早孕流产、先兆子痫、宫内生长受限和早产。形式，这影响了研究滋养层细胞侵袭和子宫螺旋动脉重塑的动物模型的适用性。大鼠表现出具有子宫内深层滋养层细胞侵袭的血绒毛膜胎盘，这一特征在人类胎盘中也观察到，该大鼠可有效地用于测试侵入性/绒毛外滋养层细胞发育的假定调节因子的生理相关性。研究目的是确定侵入性/绒毛外滋养层细胞发育和侵入性滋养层/绒毛外滋养层引导子宫的保守调节因子我们将使用单细胞 RNA 测序 (RNA-seq) 和转座酶可及染色质测序 (ATAC-seq)，对通过妊娠测序数据从子宫胎盘界面分离的细胞群进行分析。将通过强大的计算分析进行询问，并与为人类子宫胎盘界面内的细胞生成的现有数据集相集成。这项任务最好通过大鼠专家的协调努力来完成。该实验将为侵袭性滋养层/绒毛外滋养层细胞发育和滋养层引导的子宫螺旋动脉重塑提供强大的候选保守调节因子列表，以供将来分析。子宫胎盘界面的其他重要成分，包括免疫细胞、内皮细胞、基质细胞和平滑肌细胞，这些细胞对子宫胎盘的健康和成功有重要贡献从研究中获得的见解将有助于未来在人类滋养层干细胞和基因操纵大鼠模型中使用一系列功能丧失和功能获得方法进行分析。