Regulation of the Expression of Human Endogenous Retrovirus envelope genes in human trophoblasts and analysis of their function

人内源性逆转录病毒包膜基因在人滋养层中的表达调控及其功能分析

• 批准号: 298527-2012
• 负责人: Barbeau, Benoit
• 金额: $ 2.04万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505819
• 关键词: Regulation; Expression; Human; Endogenous; Retrovirus

The human genome harbours sequences, which originate from viruses known as retroviruses. It has been estimated that about 8% of human DNA is composed of these retroviral sequences. These sequences have been integrated in the genome of primates 25 million years ago. Although most of these DNA regions are no longer capable of producing viruses, some have been reported to have retained the capacity to generate viruses, which, although non-infectious, can be observed in the extracellular milieu. These viruses are termed Human Endogenous Retroviruses (HERV). The presence of HERVs in the human organism has been rarely associated with biological phenomena, although tentative links have been suggested between their presence and various forms of cancers, arthritis, multiple sclerosis and schizophrenia. Interestingly, proteins derived from HERV-related genes, termed Syncytin 1, Syncytin 2, EnvV and EnvP(b) representing the envelope proteins of ancient retroviruses could be important for the development of the placenta. Based on our previous results, we are interested in testing their involvement in placenta development through the study of the mechanism of regulation of their expression in trophoblasts (placenta-derived cells), their localisation inside the cell and by analysing their impact on differentiation of these cells and immunosuppression linked to the placenta. Several tools (including specific antibodies, new chimeric proteins and RNA interference-based RNA molecules) will be used in this study to understand the implication of these retrovirus-related proteins in the various roles that are attributed to trophoblasts. These results will bring a new light on how these HERV genes are turned on in trophoblasts and how they affect important biological processes and functions associated to the placenta. This research project should also permit to reach a better understanding of disorders related to pregnancy and anomalies in the placenta development such as preeclampsia.

人类基因组包含的序列源于逆转录病毒。据估计，大约8%的人类DNA是由这些逆转录病毒序列组成的。这些序列早在2500万年前就被整合到了灵长类动物的基因组中。虽然这些DNA区域中的大多数不再能够产生病毒，但据报道，有些区域保留了产生病毒的能力，这些病毒虽然不具有传染性，但可以在细胞外环境中观察到。这些病毒被称为人类内源性逆转录病毒（HERV）。人类机体中herv的存在很少与生物学现象联系在一起，尽管已初步提出它们的存在与各种形式的癌症、关节炎、多发性硬化症和精神分裂症之间存在联系。有趣的是，来自herv相关基因的蛋白质，称为Syncytin 1， Syncytin 2， EnvV和EnvP(b)，代表古代逆转录病毒的包膜蛋白，可能对胎盘的发育很重要。基于我们之前的研究结果，我们有兴趣通过研究它们在滋养细胞（胎盘来源的细胞）中的表达调节机制，它们在细胞内的定位，以及分析它们对这些细胞的分化和与胎盘相关的免疫抑制的影响，来测试它们在胎盘发育中的作用。本研究将使用几种工具（包括特异性抗体、新的嵌合蛋白和基于RNA干扰的RNA分子）来了解这些逆转录病毒相关蛋白在滋养层细胞的各种作用中的含义。这些结果将为了解这些HERV基因如何在滋养细胞中开启以及它们如何影响与胎盘相关的重要生物学过程和功能提供新的线索。该研究项目还应允许更好地了解与妊娠有关的疾病和胎盘发育中的异常，如先兆子痫。