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

人类基因组中含有源自逆转录病毒的序列。据估计，大约8%的人类DNA由这些逆转录病毒序列组成。这些序列已经整合到2500万年前的灵长类动物的基因组中。尽管这些DNA区域中的大多数不再能够产生病毒，但据报道，其中一些区域保留了产生病毒的能力，尽管这些病毒不具传染性，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的存在很少与生物现象有关，尽管人们初步认为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，称为Syncytin 1，Syncytin 2，EnvV和EnvP(B)，代表古代逆转录病毒的包膜蛋白，可能对胎盘的发育起重要作用。基于我们以前的结果，我们有兴趣通过研究它们在滋养细胞(胎盘来源的细胞)中表达的调节机制、它们在细胞内的定位以及通过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参与胎盘发育的作用。在这项研究中，将使用几种工具(包括特定抗体、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中的各种作用。这些结果将为这些HERV基因在滋养层细胞中如何启动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。这一研究项目还应使人们能够更好地了解与妊娠和胎盘发育异常有关的疾病，如先兆子痫。

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.