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

OVO-like 1在调节人滋养层分化中的作用

• 批准号: 9097066
• 负责人: Stephen James Renaud
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF WESTERN ONTARIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097066
• 关键词: Role; OVO; like; regulation; human

 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.

 描述（由申请人提供）：胎盘的正常发育对于胎儿的生长和生存能力至关重要。胎盘发育不良会导致多种妊娠并发症，增加母亲和新生儿的发病和死亡风险。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。 滋养层细胞的几种特殊亚型构成胎盘的上皮成分。其中一种亚型——合体滋养层——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。合体滋养层在整个妊娠过程中通过单核细胞滋养层细胞的细胞质融合不断形成。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。我们的主要目标是定义调节合胞素基因表达和合体滋养层形成的转录网络。通过微阵列分析，我们首次发现保守转录因子 OVOL1 在人类合体滋养层形成模型中被高度诱导。 OVOL1 与许多物种的上皮分化调节有关。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 OVOL1 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 OVOL1 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 OVOL1 表达时，人类滋养层细胞的分化潜力会发生什么变化。目标 2 将确定 OVOL1 如何融入控制逆转录病毒衍生基因表达以及合胞化的基因调控网络。 我们期望从目标 1 和 2 的实验中获得的信息将提供有关滋养层合胞化的相关信息，并将为胎盘发育的分子调控提供新的线索。我们还期望从这些研究中获得的信息将为我们探索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。