Atypical protein kinase C signaling and placentation

非典型蛋白激酶 C 信号转导和胎盘

• 批准号: 9765590
• 负责人: Soumen Paul
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765590
• 关键词: Adult; Biological Models; Blood; Blood Vessels; Cell Differentiation process; Cell Lineage; Cell fusion; Cell surface; Cells; Chorion; Conceptus; Cone; Defect; Development; Disease; Ectoderm; Embryo; Embryonic Development; Endothelial Cells; Ensure; Event; Experimental Models; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; GCM1 gene; Genes; Genetic; Giant Cells; Goals; Health; Hemochorial Placental Development; Hormones; Human; Impairment; Institutes; Knockout Mice; Labyrinth; Lead; Left; Maintenance; Mammals; Maternal Mortality; Maternal-Fetal Exchange; Mediating; Modeling; Molecular; Morphology; Mothers; Mus; Neuroglia; Pathway interactions; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy loss; Premature Birth; Process; Protein Isoforms; Proteins; Public Health; RNA Interference; Reproduction; Risk; Rodent; Rodent Model; Signal Transduction; Spontaneous abortion; Stem cells; Surface; Syncytiotrophoblast; Testing; Transgenic Mice; Villous; atypical protein kinase C; blastocyst; cell type; cytotrophoblast; early pregnancy; early pregnancy loss; experimental study; fetal; implantation; insight; mouse model; natural Blastocyst Implantation; placental mammal; postnatal; progenitor; selective expression; self-renewal; stem; transcription factor; trophoblast

Abstract Early pregnancy loss is a serious health concern. Defective development of the syncytiotrophoblast (SynT)- lineage, which assures placentation and establishes the fetal/maternal exchange surface, is one of the leading causes for early pregnancy loss. Furthermore, in an established pregnancy, defective development and function of SynT-lineage could lead to pregnancy-associated complications like IUGR and preeclampsia or serve as developmental causes for postnatal or adult diseases. Despite of the critical importance of SynTs, we have a poor understanding of signaling mechanisms that regulate SynT development. Especially very little is known about early human placentation process. Our studies with mouse model provide genetic evidence that loss-of atypical protein kinase C isoform, PKCλ/ι, function in trophoblast progenitors could lead to early pregnancy due to defective development of SynTs within the placental labyrinth zone. These observations led us to the central hypothesis of this proposal that PKCλ/ι)-signaling mediates a conserved function in establishing SynT development across mammalian species. The goal of this proposal is to test this hypothesis by using both transgenic mouse and human trophoblast stem cells (human TSCs) as experimental models. Two specific aims are proposed. In aim 1, using conditional PKCλ/ι knockout mouse models, we will test the hypothesis that cell-autonomous function of PKCλ/ι in trophoblast progenitors is essential for SynT development and placentation. In aim 2, using human TSCs as a model system, we will test the hypothesis that PKCλ/ι signaling is essential for both maintenance of the stem/progenitor state in hTSCs and their differentiation towards SynT lineage.

抽象的 早期怀孕丧失是一个严重的健康问题。 Syncitotophophophast（Synt）的缺陷发展 - 谱系假定位置并建立胎儿/母体交换表面，是领先的 提早怀孕的原因。此外，在既定的怀孕，有缺陷的发展和功能 同步可能会导致与妊娠相关并发症，例如IUGR和先兆子痫，或用作 产后或成人疾病的发展原因。尽管同义词的重要性至关重要，但我们的差 了解调节同步发展的信号传导机制。特别鲜为人知 人类安置过程。我们使用小鼠模型的研究提供了遗传证据表明非典型蛋白质丧失 激酶C同工型，PKCλ/i，在滋养细胞祖细胞中的功能可能导致由于缺陷而导致早期妊娠 在占地迷宫区域内的同步发展。这些观察结果使我们提出了 pkcλ/i）的这个建议 - 信号介导了一个配置的函数，以建立跨越 哺乳动物。该提案的目的是通过使用转基因小鼠和 人滋养细胞干细胞（人类TSC）作为实验模型。提出了两个具体目标。 在AIM 1中，使用条件PKCλ/i基因敲除鼠标模型，我们将测试细胞自治的假设 PKCλ/i在滋养细胞祖细胞中的功能对于同步发展和放置至关重要。 在AIM 2中，使用人类TSC作为模型系统，我们将检验以下假设：PKCλ/I信号是必不可少的 为了维持HTSC中的茎/祖细胞状态及其对同步谱系的分化。