Investigation of ERV-K-env expression and function in placentation

胎盘形成中 ERV-K-env 表达和功能的研究

• 批准号: 9789657
• 负责人: Jimi Rosenkrantz
• 金额: $ 4.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789657
• 关键词: Address; Biological; Biological Process; Cell Line; Cell fusion; Cell physiology; Cells; Cessation of life; Consensus; Consensus Sequence; Data; Defect; Development; Disease; Elements; Endogenous Retroviruses; Expression Profiling; Family; Fetus; First Pregnancy Trimester; Future; Genes; Genome; Genomics; Giant Cells; Goals; Health; Human; Human Cell Line; Human Development; Human Genome; Immune; Immunofluorescence Immunologic; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Investigation; Knowledge; Link; Macaca mulatta; Maintenance; Maternal-Fetal Exchange; Measures; Mediating; Membrane; Modeling; Molecular; Morphogenesis; Mothers; Mutate; Neonatal; Open Reading Frames; Pathologic; Personal Satisfaction; Physiological; Placenta; Placentation; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Primates; Proteins; Reproduction; Retroviridae; Role; Sampling; Small Interfering RNA; Techniques; Testing; Therapeutic; Third Pregnancy Trimester; Tissues; Transcript; Trophoblastic Cell; Viral; Viral Genes; Viral Proteins; Woman; Work; base; cell type; combat; cytokine; env Gene Products; human data; in vivo; interest; knock-down; mammalian genome; novel; prenatal; primate development; syncytin; transcriptome sequencing; trophoblast

PROJECT SUMMARY/ ABSTRACT Throughout pregnancy, normal placentation is central to prenatal development and the health of both mother and baby. Placental abnormalities are strongly associated with several common pregnancy complications, such as preeclampsia and preterm birth, responsible for ~35% of neonatal and 10% pregnancy-related deaths in women worldwide. Despite some progress in combating these diseases, our understanding of the placental abnormalities contributing to these complications is still lacking, since many of the basic molecular and cellular processes underlying normal placentation are not yet fully understood. Recently, there has been a growing interest in the biological role of endogenous retrovirus (ERV) derived proteins during early development and placentation. ERVs are endogenous viral elements found in the mammalian genome that closely resemble and are derived from ancient exogenous retroviruses. While most ERVs within the genome are highly mutated and lack the ability to express viral genes, some have been shown to contain conserved open reading frames (ORFs) and encode viral-like proteins. The most notable examples of these in humans are Syncytin-1 and Syncytin-2 in the placenta, proteins encoded by the envelope (env) gene of ERVs belonging to the ERV-W and ERV-FRD family, respectively. Syncytins possess fusogenic activity, which is critical during placentation for the normal formation and maintenance of the outer trophoblast layer at the maternal-fetal interface. Recently, a primate- specific ERV envelope protein, ERV-K-env, has also been shown to be expressed within trophoblast subpopulations during normal human placentation. This protein is derived from the ERV-K group, the youngest and most recently expanded ERV; unlike the Syncytins, ERV-K contains dozens of proviral insertions in the human genome with predicted intact ORFs. Recent studies using the ERV-K-env consensus sequence identified fusion (FD) and immunosuppression (ISD) domains closely resembling those found in exogenous retroviruses, and the inherent ability to elicit fusion and immunosuppression in other cell types. Even though ERV-K activity during early human development has been the focus of numerous studies, the native expression and function of ERV-K-env in primate placentation have largely been overlooked. The aims of the proposed studies are to assess the fusogenic role of ERV-K-env within primate trophoblasts in vitro and to characterize and elucidate changes in ERV-K-env expression within healthy and pathological placental tissues in vivo. In Aim 1, we will test the hypothesis that ERV-K-env plays a fusogenic role within isolated primate placental trophoblast cells. For Aim 2, we will test the hypothesis that ERV-K-env expression observed within the healthy placenta is significantly altered during preterm birth, specifically in a manner that is consistent with reduced ISD and/or FD function. The ultimate goals of this project are to elucidate the function of ERV-K-env in normal primate placentation, whether it has a role in common pregnancy complications, and set the stage for future therapeutic investigations targeting ERV-K-env expression in the placenta.

项目总结/摘要 在整个怀孕期间，正常的胎盘形成对产前发育和母亲双方的健康至关重要。 还有宝宝胎盘异常与几种常见的妊娠并发症密切相关，如 先兆子痫和早产，造成约35%的新生儿和10%的妊娠相关死亡， 全世界的女人。尽管在对抗这些疾病方面取得了一些进展，但我们对胎盘的了解 导致这些并发症的异常仍然缺乏，因为许多基本的分子和细胞 正常胎座形成的过程尚未完全了解。最近，越来越多的 对内源性逆转录病毒（ERV）衍生蛋白在早期发育过程中的生物学作用感兴趣， 胎座式ERV是在哺乳动物基因组中发现的内源性病毒元件，其非常类似于并且 是由古老的外源性逆转录病毒衍生而来的虽然基因组内的大多数ERV是高度突变的， 缺乏表达病毒基因的能力，有些已被证明含有保守的开放阅读框（ORF） 并编码类似病毒的蛋白质。这些在人类中最显著的例子是在哺乳动物中的合胞素-1和2。 胎盘，由属于ERV-W和ERV-FRD的ERV的包膜（env）基因编码的蛋白质 家庭，分别。合胞素具有融合活性，这在胎盘形成过程中对于正常的胎盘细胞是至关重要的。 母胎界面外滋养层的形成和维持。最近，一种灵长类动物- 还显示特异性ERV包膜蛋白ERV-K-env在滋养层内表达 在正常的人类胎盘形成过程中。这种蛋白质来源于ERV-K组，最年轻的 和最近扩展的ERV;与Syncytins不同，ERV-K在细胞中包含数十个前病毒插入物。 具有预测的完整ORF的人类基因组。最近的研究使用ERV-K-env共有序列鉴定了 融合（FD）和免疫抑制（ISD）结构域与外源性 逆转录病毒，以及在其他细胞类型中引发融合和免疫抑制的固有能力。即使 ERV-K在人类早期发育过程中的活性一直是众多研究的焦点， ERV-K-env基因在灵长类胎盘形成中的作用和功能在很大程度上被忽视。建议的目标 研究是评估ERV-K-env在体外灵长类滋养层细胞内的融合作用， 并阐明体内健康和病理性胎盘组织中ERV-K-env表达的变化。在Aim中 1，我们将检验ERV-K-env在分离的灵长类胎盘滋养层中起融合作用的假设 细胞对于目标2，我们将检验在健康胎盘中观察到的ERV-K-env表达是正常的这一假设。 在早产期间发生显著改变，特别是以与ISD和/或FD减少一致的方式 功能本课题的最终目的是阐明ERV-K-env在正常灵长类动物中的功能 胎盘是否对常见的妊娠并发症有作用，并为今后的治疗奠定基础。 针对ERV-K-env在胎盘中表达的研究。