Establishment of the Uterine-Placental Interface

子宫胎盘界面的建立

• 批准号: 10650365
• 负责人: Regan Leigh Scott
• 金额: $ 3.63万
• 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/10650365
• 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; Invaded; Kansas; Laboratories; 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; System; Therapeutic Intervention; Tissues; Training; Transcript; Universities; Uterus; Villous; biomedical scientist; candidate identification; 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.

随着妊娠的进展，胎儿不断增长的氧气和养分需求增加。为了满足这些需求，在子宫定位界面进行适应。怀孕初期，滋养细胞（TS）细胞分化并侵入子宫组织以促进子宫螺旋动脉的重塑。胎盘发育异常，滋养细胞侵袭不足会导致妊娠疾病，包括早期妊娠丧失，子痫前期，宫内内生长限制和预期出生。子宫，尤其是子宫脉管系统的侵入性滋养细胞细胞转化的失败是导致这些毁灭性的产科并发症的病因。但是，我们对侵入性滋养细胞谱系的发展的机制知之甚少。我们研究方法的基本前提是胎盘的调节中存在保护。我们将大鼠用作模型，因为与其他物种（包括小鼠）不同，大鼠表现出与人类类似的宫内滋养细胞侵袭。人类TS细胞最近已被分离并在体外传播，可以操纵以区分侵入性滋养细胞，在人类中，这些细胞被称为跨滋养细胞（EVT）细胞。人TS细胞是研究调节滋养细胞分化的分子机制的绝佳模型。我们的远程目标是确定控制侵入性滋养细胞谱系分化的保守调节器。在一项初步研究中，我们使用了大鼠子宫 - 局部界面的单细胞RNA测序（SCRNA-SEQ）来识别侵入性滋养细胞细胞谱系的候选调节剂。我们将依赖性激酶抑制剂1C（CDKN1C）确定为在大鼠和人类的侵入性滋养细胞细胞中独特表达的保守转录本。 CDKN1C是几种发育系统中细胞增殖，内置和分化的关键调节剂。在AIM 1中，将使用功能丧失方法来研究CDKN1C在人TS细胞分化中的参与到侵袭性EVT细胞谱系中。我们将检查受CDKN1C影响的结构，转录和功能过程。在AIM 2中，我们利用功能丧失的大鼠模型来检查CDKN1C在胎盘生理环境中的作用。该项目将在Michael J Soares博士和由杰出的生物医学科学家组成的指导团队的指导下在堪萨斯大学医学中心（KUMC）完成。已经制定了培训计划，以促进设计和执行实验所需的技术能力和批判性思维技能的发展，从而有效解决有意义的生物学问题。 KUMC的SOARES实验室，繁殖和围产期研究研究所以及病理学和实验室医学系代表了丰富的科学环境，该环境将提供出色的研究生培训和研究机会，以获取对侵入性滋养滋养细胞谱系的新见解，并建立了子宫植物植入术的界面。