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 早孕流产是一个严重的健康问题。 确保胎盘形成并建立胎儿/母体交换表面的谱系是主要的因素之一 此外，在已怀孕的情况下，胎儿的发育和功能有缺陷。 SynT 谱系可能导致妊娠相关并发症，如 IUGR 和先兆子痫，或作为 产后或成人疾病的发育原因 尽管 SynT 至关重要，但我们的研究还很有限。 对调节 SynT 发育的信号机制的了解尤其少。 我们对小鼠模型的研究提供了非典型蛋白质丢失的遗传证据。 滋养层祖细胞中的激酶 C 同种型 PKCλ/ι 功能可能因缺陷而导致早孕 SynTs 在胎盘迷路区内的发育这些观察结果使我们得出了以下的中心假设。 该提议认为 PKCλ/ι)-信号介导在建立 SynT 发展过程中的保守功能 该提案的目标是通过使用转基因小鼠和哺乳动物来测试这一假设。 提出了两个具体目标。 在目标 1 中，使用条件 PKCλ/ι 敲除小鼠模型，我们将检验细胞自主性的假设 滋养层祖细胞中 PKCλ/ι 的功能对于 SynT 发育和胎盘形成至关重要。 在目标 2 中，使用人类 TSC 作为模型系统，我们将测试 PKCλ/ι 信号传导至关重要的假设 用于维持 hTSC 中的干细胞/祖细胞状态及其向 SynT 谱系的分化。