Atypical protein kinase C signaling and placentation

摘要 早孕丢失是一个严重的健康问题。合体滋养层细胞发育缺陷-- 血统，它确保胎盘形成并建立胎儿/母亲的交换面，是领先的 导致早孕丢失的原因。此外，在已确定的怀孕期间，有缺陷的发育和功能 SYNT血统可能导致与妊娠相关的并发症，如IUGR和先兆子痫，或作为 出生后或成人疾病的发育原因。尽管Synts至关重要，但我们有一个很差的 了解调节SYNT发育的信号机制。尤其是对早期的情况知之甚少 人体胎盘形成过程。我们对小鼠模型的研究提供了非典型蛋白丢失的遗传学证据 蛋白激酶C亚型λ/ι在滋养层祖细胞中的功能可能导致早孕 胎盘迷路带内合并症的发生这些观察结果使我们得出了一个中心假设： 这一建议认为，PKC-λ/ι)-信令在建立SYNT发育过程中起着保守的作用 哺乳动物物种。这项提议的目标是通过使用转基因小鼠和 以人滋养层干细胞为实验模型。提出了两个具体目标。 在目标1中，使用有条件的PKCλ/ι基因敲除小鼠模型，我们将检验细胞自主性的假设 蛋白激酶Cλ/ι在滋养层祖细胞中的功能对于突触发育和胎盘形成是必不可少的。 在目标2中，以人胚胎干细胞为模型系统，我们将检验pkcλ/ι信号转导是必不可少的这一假设。 用于维持hTSCs的干/祖细胞状态和向SYNT谱系分化。

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.