Signaling at the Uterine Placental Interface

子宫胎盘界面的信号传导

基本信息

批准号：
10752302
负责人：
Mikaela Elizabeth Simon
金额：
$ 3.62万
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：
2023
资助国家：
美国
起止时间：
2023-07-17 至 2027-07-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752302
关键词：
Abate Activins Address Affect Biological Blood flow CRISPR/Cas technology Cell Communication Cell Differentiation process Cell Lineage Cell Proliferation Cells Complex Critical Thinking Decidua Development Diagnostic Disease Embryo Environment Exhibits Fetal Development Fetal Growth Fetal Growth Retardation Fetus Follistatin Genomics Goals Health Hemochorial Placental Development Human In Vitro Invaded Kansas Laboratories Location Medical center Medicine Mentors Modeling Molecular Mothers Mus Nutrient Pathogenesis Pathology Physiological Physiology Placenta Placentation Population Pre-Eclampsia Pregnancy Pregnancy Complications Premature Birth Process Rattus Regulation Regulatory Pathway Research Rodent Role Science Scientist Signal Transduction Site Spiral Artery of the Endometrium Study models Therapeutic Intervention Training Transcript Universities Uterus Villous antagonist candidate identification early pregnancy loss embryo cell experimental study female fertility gain of function genome editing in vivo insight loss of function migration mutant negative affect obstetrical complication reproductive restraint shear stress single-cell RNA sequencing skills stem stem cell differentiation transcriptomics trophoblast trophoblast stem cell

项目摘要

PROJECT SUMMARY/ABSTRACT During pregnancy, maternal and extraembryonic cells interact at the uterine-placental interface, facilitating adaptations that promote fetal growth. Trophoblast stem (TS) cells differentiate and invade into the uterus during pregnancy. When invasive trophoblast cells fail to invade and remodel the uterine spiral arteries this leads to obstetrical complications such as early pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth. There is little known about the mechanisms of invasive trophoblast cell lineage development. The long-term goal of our research is to identify conserved regulators of invasive trophoblast cell lineage development and its contributions to diseases of pregnancy. We utilize the rat model because like the human it exhibits deep intrauterine trophoblast cell invasion, unlike the shallow invasion observed in the mouse. We also use human TS cells that can be manipulated to differentiate into invasive trophoblast cells, which are known as extravillous trophoblast (EVT) cells in the human. Human TS are a useful model for investigating molecular mechanisms regulating trophoblast cell differentiation. To identify candidate regulators of the invasive trophoblast cell lineage, our lab performed single-cell RNA sequencing (scRNA-seq) of the rat uterine-placental interface. We identified follistatin-like 3 (FSTL3) as a conserved transcript uniquely expressed in invasive trophoblast cells of the rat and human. FSTL3 is an antagonist of activin signaling. Evidence exists for activin and FSTL3 involvement in the regulation of trophoblast cell proliferation, survival, migration, and invasion. In Aim1, we will utilize loss-of-function and gain-of-function approaches to investigate the involvement of activin and FSTL3 in the regulation of human TS cell differentiation into the EVT cell lineage. We will examine structural, transcriptomic, and functional processes affected by activin-FSTL3 dysregulation. In Aim 2, we will evaluate the role of FSTL3 in development of the invasive trophoblast cell lineage within the rat hemochorial placenta. We have generated an FSTL3 null rat model using CRISPR/ Cas9 genome editing. These experiments will permit analysis of the regulatory role of FSTL3 in a physiological context. 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 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 Reproductive and Developmental Sciences, and the Department of Pathology and Laboratory Medicine at KUMC represent a rich scientific environment that will provide the applicant with outstanding graduate training and a research opportunity to gain fundamental new insights into the regulation of female fertility.

项目概要/摘要在怀孕期间，母体细胞和胚胎外细胞在子宫胎盘界面相互作用，促进促进胎儿生长的适应。滋养层干细胞 (TS) 分化并侵入子宫怀孕期间。当侵入性滋养层细胞无法侵入并重塑子宫螺旋动脉时，导致产科并发症，如早孕流产、先兆子痫、宫内生长受限、和早产。关于侵袭性滋养层细胞谱系的机制知之甚少发展。我们研究的长期目标是确定侵袭性滋养层细胞的保守调节因子谱系发育及其对妊娠疾病的贡献。我们利用大鼠模型是因为与在人类中观察到的浅层侵入不同，它表现出子宫内深层滋养层细胞侵入。老鼠。我们还使用可被操纵分化为侵袭性滋养层细胞的人类 TS 细胞，它们在人类中被称为绒毛外滋养层（EVT）细胞。人类 TS 是一个有用的模型研究调节滋养层细胞分化的分子机制。确定候选监管机构为了研究侵袭性滋养层细胞谱系，我们的实验室对大鼠进行了单细胞 RNA 测序 (scRNA-seq) 子宫胎盘界面。我们将卵泡抑素样 3 (FSTL3) 鉴定为独特的保守转录本在大鼠和人的侵袭性滋养层细胞中表达。 FSTL3 是激活素信号传导的拮抗剂。有证据表明激活素和 FSTL3 参与调节滋养层细胞增殖、存活、迁徙、入侵。在 Aim1 中，我们将利用功能丧失和功能获得方法来研究激活素和 FSTL3 参与调节人 TS 细胞分化为 EVT 细胞血统。我们将检查受 activin-FSTL3 影响的结构、转录组和功能过程失调。在目标 2 中，我们将评估 FSTL3 在侵袭性滋养层细胞发育中的作用大鼠血绒质胎盘内的谱系。我们使用 CRISPR/Cas9 生成了 FSTL3 无效大鼠模型基因组编辑。这些实验将允许分析 FSTL3 在生理学中的调节作用语境。该项目将在堪萨斯大学医学中心（KUMC）的指导下完成由 Michael J Soares 博士和杰出科学家组成的导师团队组成。已制定培训计划促进设计和执行所需的技术熟练程度和批判性思维技能的发展有效解决有意义的生物学问题的实验。苏亚雷斯实验室生殖与发育科学研究所、病理与实验室教研室 KUMC 的医学代表着丰富的科学环境，将为申请人提供出色的研究生培训和研究机会，以获得对女性监管的基本新见解生育能力。