Signaling at the Uterine Placental Interface

子宫胎盘界面的信号传导

• 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
• 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

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.

项目总结/摘要 在妊娠期间，母体细胞和胚外细胞在子宫-胎盘界面相互作用， 促进胎儿生长的适应。滋养层干细胞（TS）分化并侵入子宫 孕期当侵袭性滋养层细胞不能侵袭和重塑子宫螺旋动脉时， 导致产科并发症，例如早孕流产、先兆子痫、子宫内生长受限， 和早产目前对滋养层细胞系侵袭性的机制还知之甚少 发展我们研究的长期目标是鉴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影响。我们使用大鼠模型，因为 人子宫内膜癌表现为子宫内滋养层细胞的深层浸润，而不像在人子宫内膜癌中观察到的浅层浸润。 老鼠.我们还使用了人类TS细胞，它可以被操纵分化成侵袭性滋养层细胞， 其在人体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 在侵袭性滋养层细胞谱系中，我们的实验室对大鼠进行了单细胞RNA测序（scRNA-seq）， 子宫胎盘界面我们鉴定了卵泡抑素样3（FSTL 3）作为一个保守的转录本， 在大鼠和人的侵袭性滋养层细胞中表达。FSTL 3是激活素信号传导的拮抗剂。 存在激活素和FSTL 3参与滋养层细胞增殖、存活 迁徙和入侵在目标1中，我们将利用功能丧失和功能获得方法来研究 激活素和FSTL 3参与人TS细胞分化为EVT细胞的调节 脉我们将研究激活素FSTL 3影响的结构、转录组和功能过程 失调在目的2中，我们将评估FSTL 3在侵袭性滋养层细胞发育中的作用。 大鼠血绒膜胎盘内的谱系。我们已经使用CRISPR/ Cas9产生了FSTL 3无效大鼠模型， 基因组编辑这些实验将允许分析FSTL 3在生理学上的调节作用。 上下文该项目将在堪萨斯大学医学中心（KUMC）的指导下完成 迈克尔·J·苏亚雷斯博士和一个由杰出科学家组成的指导团队。制定了培训计划， 促进必要的技术专业知识和批判性思维能力的发展，以设计和执行 一个有效地解决有意义的生物学问题的实验。苏亚雷斯实验室 生殖和发育科学研究所，病理学和实验室 医学在KUMC代表了一个丰富的科学环境，将提供优秀的申请人 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