Establishment of the Uterine-Placental Interface

子宫胎盘界面的建立

• 批准号: 10315944
• 负责人: Regan Leigh Scott
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315944
• 关键词: Address; Biological; Blood flow; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Communication; Critical Thinking; Cyclin-Dependent Kinase Inhibitor; Decidua; Development; Diagnostic; Disease; Environment; Event; Exhibits; Failure; Fetal Growth; Fetal Growth Retardation; Fetus; Genes; Goals; Health; Hemochorial Placental Development; Human; In Vitro; Institutes; Invaded; Kansas; Laboratories; Lead; Medical center; Medicine; Mentors; Modeling; Molecular; Mothers; Mus; Nutrient; Oxygen; Pathogenesis; Pathology; Perinatal; Physiological; Physiology; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Process; Rattus; Regulation; Reproduction; Research; Research Proposals; Rodent; Role; Site; Spiral Artery of the Endometrium; Structure; System; Therapeutic Intervention; Tissues; Training; Transcript; Universities; Uterus; base; biomedical scientist; cell transformation; early pregnancy loss; experimental study; genome editing; in vivo; insight; loss of function; mutant; obstetrical complication; pregnancy disorder; shear stress; single-cell RNA sequencing; skills; stem cell differentiation; transcriptomics; trophoblast; trophoblast stem cell

As pregnancy progresses, the oxygen and nutrient needs of the growing fetus increase. To accommodate these needs, adaptations occur at the uterine-placental interface. Early in pregnancy, trophoblast stem (TS) cells differentiate and invade into the uterine tissue to facilitate remodeling of uterine spiral arteries. Abnormal placenta development with insufficient trophoblast invasion leads to pregnancy disorders including early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth. The failure of invasive trophoblast cell transformation of the uterus and especially the uterine vasculature is the causative event leading to these devastating obstetrical complications. However, we know little about the mechanisms underlying development of the invasive trophoblast cell lineage. The underlying premise of our research approach is that conservation exists in the regulation of placentation. We utilize the rat as a model because unlike other species, including the mouse, the rat exhibits deep intrauterine trophoblast cell invasion similar to the human. Human TS cells have recently been isolated and propagated in vitro and can be manipulated to differentiate into invasive trophoblast, which in the human are referred to as extravillous trophoblast (EVT) cells. Human TS cells are an excellent model for investigating molecular mechanisms regulating trophoblast cell differentiation. Our long-range goal is to identify conserved regulators controlling differentiation of the invasive trophoblast cell lineage. In a preliminary study, we used single-cell RNA sequencing (scRNA-seq) of the rat uterine-placental interface to identify candidate regulators of the invasive trophoblast cell lineage. We identified cyclin dependent kinase inhibitor 1C (CDKN1C) as a conserved transcript uniquely expressed in invasive trophoblast cells of the rat and human. CDKN1C is a key regulator of cell proliferation, endoreduplication, and differentiation in several developmental systems. In Aim 1, a loss-of-function approach will be used to investigate the involvement of CDKN1C in human TS cell differentiation into the invasive EVT cell lineage. We will examine structural, transcriptomic, and functional processes impacted by CDKN1C. In Aim 2, we utilize a loss-of-function rat model to examine the role of CDKN1C in the physiological context of placentation. This project will be completed at the University of Kansas Medical Center (KUMC) under the guidance of Dr. Michael J Soares and a mentoring team of outstanding biomedical scientists. A training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills necessary to devise and execute experimentation that effectively addresses a meaningful biological question. The Soares Laboratory, the Institute for Reproduction and Perinatal Research, and the Department of Pathology and Laboratory Medicine at KUMC represent a rich scientific environment that will provide outstanding graduate training and a research opportunity to gain new insights into the regulation of the invasive trophoblast cell lineage and the establishment of the uterine-placental interface.

随着怀孕的进展，胎儿对氧气和营养的需求也在增加。为了适应这些需求，适应性发生在子宫-胎盘界面。妊娠早期，滋养细胞干细胞（trophoblast stem， TS）分化并侵入子宫组织，促进子宫螺旋动脉的重塑。滋养细胞侵袭不足的胎盘发育异常可导致妊娠障碍，包括早孕流产、先兆子痫、宫内生长受限和早产。子宫，特别是子宫血管浸润性滋养细胞转化的失败是导致这些毁灭性的产科并发症的致病事件。然而，我们对侵袭性滋养细胞谱系的发展机制知之甚少。我们的研究方法的基本前提是，保护存在于胎盘的调节。我们利用大鼠作为模型，因为与其他物种（包括小鼠）不同，大鼠表现出与人类相似的子宫内深层滋养细胞侵袭。人类TS细胞最近被分离出来并在体外繁殖，并且可以被操纵分化为侵袭性滋养细胞，在人类中被称为外滋养细胞（EVT）。人类TS细胞是研究滋养细胞分化调控分子机制的良好模型。我们的长期目标是确定控制侵袭性滋养细胞谱系分化的保守调节因子。在一项初步研究中，我们使用大鼠子宫-胎盘界面的单细胞RNA测序（scRNA-seq）来鉴定侵袭性滋养细胞谱系的候选调节因子。我们发现细胞周期蛋白依赖性激酶抑制剂1C （CDKN1C）是在大鼠和人的侵袭性滋养细胞中唯一表达的保守转录物。CDKN1C是几个发育系统中细胞增殖、内复制和分化的关键调节因子。在Aim 1中，将使用功能缺失方法来研究CDKN1C在人类TS细胞分化为侵袭性EVT细胞谱系中的作用。我们将研究受CDKN1C影响的结构、转录组学和功能过程。在Aim 2中，我们利用功能丧失大鼠模型来研究CDKN1C在胎盘生理环境中的作用。该项目将在堪萨斯大学医学中心（KUMC）完成，由Michael J Soares博士和优秀生物医学科学家组成的指导团队指导。制定了一项培训计划，以促进技术熟练程度和批判性思维技能的发展，这些技能是设计和执行有效解决有意义的生物学问题的实验所必需的。苏亚雷斯实验室，生殖和围产期研究所，以及病理和检验医学系代表了一个丰富的科学环境，将提供优秀的研究生培训和研究机会，以获得新的见解，以调节侵袭性滋养细胞谱系和建立子宫-胎盘界面。