Role of OVO-like 1 in the regulation of human trophoblast differentiation

 描述（由申请方提供）：胎盘的正常发育对胎儿的生长和存活至关重要。胎盘发育不良会引起几种妊娠并发症，增加母亲和新生儿的发病率和死亡率。更好地了解控制正常胎盘发育的分子网络将显着提高我们对这些妊娠并发症发病机制的理解。 滋养层细胞的几个特化亚型构成胎盘的上皮成分。一种亚型-合胞体滋养层-是一种独特的多核谱系，形成母体和胎儿循环之间的主要屏障。合体滋养层细胞在整个妊娠过程中通过单核细胞滋养层细胞的胞质融合而不断形成。融合是由人内源性逆转录病毒衍生的合胞素基因催化的复杂过程。我们的主要目标是确定转录网络，调节合胞体蛋白基因的表达和合胞体滋养层的形成。通过微阵列分析，我们是第一个确定，保守的转录因子OVOL 1是高度诱导的人类合体滋养层形成的模型。OVOL 1在许多物种中参与上皮分化的调节;然而，其在人类滋养层分化中的作用尚不清楚。在初步分析中，我们观察到OVOL 1的缺失对滋养层细胞的分化能力具有有趣的影响。为了更彻底地评估OVOL 1在合体滋养层形成中的作用，我们提出了两个目标中概述的引人注目的实验。目标1将确定当操纵OVOL 1表达时，人类滋养层细胞的分化潜力会发生什么变化。目的2将确定OVOL 1如何融入控制逆转录病毒衍生基因表达的基因调控网络，从而实现合胞化。 我们期望从目标1和2的实验中获得的信息将提供滋养层合胞化的相关信息，并将揭示胎盘发育的分子调控。我们还希望从这些研究中获得的信息将为我们了解正常和病理妊娠中控制胎盘发育的分子信号提供重要基础。

 DESCRIPTION (provided by applicant): Proper development of the placenta is paramount for fetal growth and viability. Maldevelopment of the placenta causes several complications of pregnancy, increasing the risk of morbidity and mortality for both mothers and newborn babies. A better understanding of the molecular networks that govern normal placental development will significantly improve our understanding of the pathogenesis of these pregnancy complications. Several specialized subtypes of trophoblast cells comprise the epithelial component of the placenta. One subtype - syncytiotrophoblast - is a unique, multinucleated lineage that forms the primary barrier between maternal and fetal circulations. Syncytiotrophoblast is continuously formed throughout pregnancy by cytoplasmic fusion of mononuclear cytotrophoblast cells. Fusion is a complex process catalyzed by human endogenous retrovirus-derived syncytin genes. Our primary objective is to define transcriptional networks that regulate the expression of syncytin genes and syncytiotrophoblast formation. Through microarray analysis, we are the first to identify that the conserved transcription factor OVOL1 is highly induced in a model of human syncytiotrophoblast formation. OVOL1 has been implicated in the regulation of epithelial differentiation in many species; however, its role in human trophoblast differentiation is not known. In preliminary analyses, we observed that depletion of OVOL1 has intriguing effects on the differentiation capacity of trophoblast cells. To more thoroughly assess the role of OVOL1 in syncytiotrophoblast formation, we propose compelling experiments outlined in two Aims. Aim 1 will determine what happens to the differentiation potential of human trophoblast cells when OVOL1 expression is manipulated. Aim 2 will determine how OVOL1 fits into a gene regulatory network controlling retrovirus-derived gene expression and consequently, syncytialization. We expect information accrued from experiments in Aims 1 and 2 will provide pertinent information on trophoblast syncytialization, and will shed new light on the molecular regulation of placental development. We also expect that the information garnered from these studies will provide an important foundation in our quest to understand the molecular signals governing placental development in both normal and pathological pregnancies.