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: 8824369
• 负责人: Stephen James Renaud
• 金额: $ 0.64万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824369
• 关键词: Binding; Biological; Blood Circulation; Calculi; Cell Lineage; Cell fusion; Cells; Complex; DNA Microarray Chip; Data; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Fetal Development; Fetal Growth; Fetal Viability; Foundations; Gene Expression; Genes; HERVs; Health; Healthcare Systems; Human; In Situ; Intervention; Light; Link; Microarray Analysis; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Mothers; Neuroglia; Newborn Infant; Organ; Pathogenesis; Pattern; Placenta; Placentation; Pregnancy; Pregnancy Complications; Process; RNA Interference; Regulation; Regulator Genes; Reporting; Retroviridae; Risk; Role; Signal Transduction; Syncytiotrophoblast; System; Tissues; Transcriptional Regulation; United States; Viral; Work; Zinc Fingers; base; cell type; cost; cytotrophoblast; env Gene Products; fetal; fusion gene; improved; insight; interest; mortality; novel; public health relevance; research study; success; syncytin; transcription factor; trophoblast

 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)：胎盘的正常发育对胎儿的生长和存活至关重要。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率和死亡率。更好地了解控制正常胎盘发育的分子网络将极大地提高我们对这些妊娠并发症的发病机制的理解。滋养细胞的几种特殊亚型构成了胎盘的上皮性成分。合体滋养层细胞是一种独特的多核细胞系，构成了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。融合是一个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调控合胞素基因表达和合体滋养层细胞形成的转录网络。通过基因芯片分析，我们首次证实在人合体滋养层细胞形成模型中高度诱导保守的转录因子OVOL1。OVOL1在许多物种中参与了上皮分化的调控，但其在人类滋养层细胞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在合体滋养细胞形成中的作用，我们提出了两个目标概述的令人信服的实验。目的1将确定当OVOL1表达被操纵时，人滋养层细胞的分化潜能发生了什么变化。目的2将确定OVOL1如何与控制逆转录病毒衍生基因表达的基因调控网络相适应，从而实现合胞化。我们期望从AIMS 1和AIMS 2中获得的信息将提供关于滋养层细胞合胞化的相关信息，并将为胎盘发育的分子调控提供新的线索。我们还希望从这些研究中获得的信息将为我们寻求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的基础。