Hippo Signaling Effector and Placentation

Hippo 信号传导效应器和放置

• 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
• 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

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 早期妊娠丧失会影响植入妊娠的15-20％。这些怀孕损失中的大多数 发生在妊娠中期和滋养细胞祖细胞的有缺陷的发展中，这确保了胚胎 植入和胎盘是早期妊娠丧失的主要原因之一。但是，我们很贫穷 了解调节滋养细胞祖细胞自我更新，分化和的分子机制 在早期植入后胚胎中的功能。我们发表的初步研究表明，河马信号传导 效应子，转录因子tead4在哺乳动物物种的滋养细胞祖细胞中保守，是一种 在哺乳动物早期发育期间，关键的调节剂指定和维持滋养细胞细胞谱系。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 专门参与调节滋养细胞祖细胞的自我更新和分化后植入后胎盘 发展。此外，我们还将测试这些机制的改变是否与复发有关 怀孕丧失（RPL）。 提出了三个具体目标。 AIM 1将研究突变小鼠模型，以测试Tead4的假设 在早期植入后胚胎中调节滋养细胞茎状祖细胞（TSPC）自我更新。 AIM 2将检验以下假设，即Tead4在谱系特异性滋养细胞中的细胞自主功能 祖细胞确保正确发展分化的滋养细胞细胞并形成母亲界面。 在AIM 3中，我们将测试TEAD4在人类原发性细胞增多质细胞（CTB）和CTB-中的功能重要性 衍生的人类滋养细胞干细胞（TSC）。我们还将招募有复发妊娠史的患者 损失（RPL）分离CTB并建立患者特异性TSC。目的是检验Tead4调节的假设 在发育中的人胎盘中的CTB祖细胞的自我更新和TEAD4的功能有缺陷是分子原因 对于无法解释的（特发性）RPL的子集。