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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.

母胎界面是子宫和胎盘结构合作促进胎儿发育的动态部位。大鼠、小鼠和人类都有绒毛膜胎盘。滋养细胞是胎盘的实质细胞，具有分化为特化细胞类型的能力，包括具有侵入性的细胞，具有进入脉管系统和重建子宫螺旋动脉的潜力。在人类中，这些侵袭性滋养细胞被称为绒毛外滋养细胞。滋养细胞侵袭的中断和滋养细胞引导的子宫螺旋重构是“产科大综合征”的核心，包括早孕丢失、先兆子痫、宫内生长受限和早产。绒毛膜胎盘有不同的形态，这影响了研究滋养细胞侵袭和子宫螺旋动脉重构的动物模型的适用性。与小鼠不同的是，大鼠的胎盘具有深层的子宫滋养细胞浸润，这一特征在人类胎盘中也观察到。大鼠可以有效地用于测试侵袭性/绒毛外滋养细胞发育的假定调节因子的生理相关性。我们研究的长期目标是确定浸润性/绒毛外滋养细胞发育和浸润性滋养细胞/绒毛外滋养细胞引导的子宫螺旋动脉重构的保守调节因子。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）测定从妊娠大鼠子宫-胎盘界面分离的细胞群。测序数据将通过强大的计算分析进行查询，并与人类子宫-胎盘界面内细胞产生的现有数据集相结合。这项任务最好通过大鼠胎盘专家的协调努力和滋养细胞转录组的计算分析来完成。该实验将为今后的分析提供一个强有力的候选保守的侵袭性滋养细胞/绒毛外滋养细胞发育和滋养细胞引导的子宫螺旋动脉重塑的调节因子列表。此外，我们将对子宫-胎盘界面的其他重要成分，包括免疫细胞、内皮细胞、间质细胞和平滑肌细胞有新的认识，这些细胞对妊娠的健康和成功有重要的贡献。从调查中获得的见解将推动未来在人类滋养细胞干细胞和基因操纵大鼠模型中使用功能丧失和功能获得方法的管道分析。