Hippo Signaling Effector and Placentation

Hippo 信号传导效应器和放置

基本信息

批准号：
10610860
负责人：
Soumen Paul
金额：
$ 45.53万
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：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610860
关键词：
Affect Blood Vessels Cell Lineage Cells Chorion Conceptus Cone Defect Development Disease Ectoderm Embryo Ensure Fetal Growth Retardation First Pregnancy Trimester Gases Gene Expression Gene Expression Regulation Genetic Transcription Goals Hormone secretion Human Impairment Knockout Mice Laboratories Maintenance Maternal Mortality Maternal-Fetal Exchange Mediating Molecular Mothers Mus Nutrient Patient Recruitments Patients Placenta Placentation Population Pre-Eclampsia Pregnancy Pregnancy loss Premature Birth Primordium Process Public Health Publishing Recording of previous events Recurrence Reproduction Research Signal Transduction Specific qualifier value Testing blastocyst conditional knockout cytotrophoblast early pregnancy loss gene conservation implantation insight mouse model mutant mouse model natural Blastocyst Implantation pregnancy failure progenitor programs self-renewal stem stem cells transcription factor trophoblast trophoblast stem cell

项目摘要

Abstract Early pregnancy loss affects 15-20% of implantation-confirmed pregnancies. Majority of these pregnancy losses occur during first trimester and defective development of trophoblast progenitors, which assures embryo implantation and placentation, is one of the leading causes for early pregnancy loss. However, we have a poor understanding of molecular mechanisms that regulate trophoblast progenitor self-renewal, differentiation and function in early postimplantation embryos. Our published and preliminary studies establish that hippo signaling effector, transcription factor TEAD4 is conserved in trophoblast progenitors across mammalian species and is a critical regulator to specify and maintain the trophoblast cell lineage during early mammalian development. The overarching goal of this proposal is to further define TEAD4-mediated conserved molecular mechanisms that are specifically involved in regulating trophoblast progenitor self-renewal and differentiation during post-implantation placenta development. In addition, we will also test whether alteration of those mechanisms is associated with recurrent pregnancy loss (RPL). Three specific aims are proposed. Aim 1 will study mutant mouse models to test the hypothesis that TEAD4 regulates trophoblast stem-like progenitor cell (TSPC) self-renewal in early postimplantation embryos. Aim 2 will test the hypothesis that cell-autonomous function of TEAD4 in lineage-specific trophoblast progenitors ensures proper development of differentiated trophoblast cells and formation of the maternal-fetal interface. In Aim 3, we will test functional importance of TEAD4 in human primary cytotrophoblasts (CTBs) and CTB- derived human trophoblast stem cells (TSCs). We will also recruit patients with known history of recurrent pregnancy loss (RPL) to isolate CTBs and establish patient-specific TSCs. The goal is to test the hypothesis that TEAD4 regulates self-renewal of CTB progenitors in a developing human placenta and defective function of TEAD4 is the molecular cause for a subset of unexplained (idiopathic) RPLs.

抽象的早期妊娠流产影响 15-20% 的植入确认妊娠。大多数流产发生在妊娠早期和滋养层祖细胞发育缺陷，这确保了胚胎植入和胎盘是早期妊娠流产的主要原因之一。然而，我们有一个贫穷的了解调节滋养层祖细胞自我更新、分化和着床后早期胚胎的功能。我们已发表的初步研究表明河马信号传导作为效应子，转录因子 TEAD4 在哺乳动物物种的滋养层祖细胞中是保守的，并且是一个在哺乳动物早期发育过程中指定和维持滋养层细胞谱系的关键调节因子。这该提案的总体目标是进一步定义 TEAD4 介导的保守分子机制特别参与调节胎盘植入后滋养层祖细胞的自我更新和分化发展。此外，我们还将测试这些机制的改变是否与复发相关妊娠丢失（RPL）。提出了三个具体目标。目标 1 将研究突变小鼠模型，以检验 TEAD4 的假设调节早期植入后胚胎中滋养层干样祖细胞 (TSPC) 的自我更新。目标 2 将检验 TEAD4 在谱系特异性滋养层中的细胞自主功能的假设祖细胞确保分化的滋养层细胞的正常发育和母胎界面的形成。在目标 3 中，我们将测试 TEAD4 在人类原代细胞滋养层 (CTB) 和 CTB- 中的功能重要性。衍生的人类滋养层干细胞（TSC）。我们还将招募已知有复发性妊娠史的患者损失（RPL）来分离 CTB 并建立患者特异性 TSC。目标是检验 TEAD4 调节的假设发育中的人类胎盘中 CTB 祖细胞的自我更新和 TEAD4 功能缺陷是分子原因对于无法解释的（特发性）RPL 的子集。