Atypical protein kinase C signaling and placentation

摘要 早孕流产是一个严重的健康问题。合胞体滋养层（SynT）发育缺陷- 确保胎盘形成并建立胎儿/母体交换表面的血统是主要的 早期妊娠丢失的原因此外，在一个既定的怀孕，有缺陷的发展和功能， 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SynTs至关重要，但我们有一个穷人 了解调节SynT发育的信号传导机制。尤其是对早期的 人类胎盘形成过程我们对小鼠模型的研究提供了遗传学证据， 滋养层祖细胞中的激酶C亚型，PKCλ/ι，功能可能导致早孕， 胎盘迷路区内SynTs的发展。这些观察使我们得出了一个中心假设， 这一提议认为，PKC（λ/1）-信号传导介导了在建立跨膜SynT发育中的保守功能， 哺乳动物物种。本提案的目的是通过使用转基因小鼠和 人滋养层干细胞（人TSC）作为实验模型。提出了两个具体目标。 在目标1中，使用条件性PKCλ/ι敲除小鼠模型，我们将检验细胞自主表达PKC λ/ι的假设。 在滋养层祖细胞中PKCλ/1的功能对于SynT发育和胎盘形成是必需的。 在目标2中，使用人TSCs作为模型系统，我们将检验PKCλ/1信号传导是必需的这一假设。 用于维持hTSCs中的干/祖细胞状态及其向SynT谱系的分化。

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.