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: 9903417
• 负责人: Soumen Paul
• 金额: $ 22.95万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903417
• 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; 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; stem cells; 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.

摘要