Regulation of expression and functions of endogenous retrovirus envelope proteins

人类基因组含有序列，这些序列起源于被称为逆转录病毒的病毒，并在数百万年前整合了灵长类动物的基因组。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，尽管代表古老逆转录病毒包膜蛋白的四种Herv蛋白-1、Syncytin-2、EnvK和EnvP(B)对胎盘和/或骨骼肌的发育可能是重要的。有趣的是，等效鼠ERV包膜蛋白，称为合胞素-A和合胞素-B，已经被发现并被认为也参与了小鼠胎盘和骨骼肌的发育/形成。我们的长期目标是更好地了解ERV被膜在不同生物学过程中的调节模式和功能，更准确地说，在这个建议中，我们的短期目标是通过研究这些蛋白在滋养层细胞(胎盘衍生细胞)和成肌细胞(肌肉细胞)中表达的调控机制，来具体研究这些蛋白在人/鼠胎盘发育和骨骼肌形成中的作用。不同的调控机制正在探索中，并基于我们实验室的初步结果和之前对HIV-1的研究。我们还将研究这些蛋白质如何通过与受体相互作用来调节其功能，以及这些相互作用可能如何受到其他细胞蛋白质的影响。这些相互作用将在两个不同细胞之间相互作用的背景下进行研究，也将在被称为外切体的循环脂质球体与靶细胞之间相互作用的背景下进行研究。最后，这些不同的蛋白质与其调节免疫反应的能力有关的功能将在基于细胞和外体的相互作用中再次被机械地检验。在这项研究中，将使用几种最先进的方法(包括修改的(假型)病毒粒子、外小体的分离和分析、基于RNA干扰的RNA分子和CRISPR)，以了解这些逆转录病毒相关蛋白质在滋养层细胞和成肌细胞中的各种作用。目前的研究计划将提供重要的新技能、知识和专业知识，对牵连的HQP未来的研究生涯将是有价值的。我们研究的影响将是重要的，因为我们的原始方法将揭示这些Herv基因是如何启动的，以及它们如何影响两个不同的重要生物学过程和对其功能的影响。

The human genome harbours sequences, which originate from viruses known as retroviruses and which have integrated the genome of primates several millions of year 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 four hERV proteins termed Syncytin-1, Syncytin-2, EnvK and EnvP(b) representing the envelope proteins of ancient retroviruses could be important for the development of the placenta and/or skeletal muscles. Interestingly, equivalent mouse ERV (mERV) envelope proteins, termed Syncytin-A and Syncytin-B have been identified and suggested to also participate in the development/formation of the murine placenta and skeletal muscles.Our long-term objective is to better understand the mode of regulation and the function of ERV envelopes in different biological processes, More precisely, in this proposal, our short-term objectives are to specifically examine the involvement of these proteins in human/mouse placenta development and skeletal muscle formation through the study of the mechanism of regulation of their expression in trophoblasts (placenta-derived cells) and myoblasts (muscle cells). Different mechanisms of regulation are being explored and are based on preliminary results from our lab and previous studies on HIV-1. We will also look at how these proteins mediate their function by interacting with receptors and how these interactions might be affected by the contribution of other cellular proteins. These interactions will be studied in the context of the interaction between two different cells but also in the context of the interaction between circulating lipidic spheres known as exosomes with target cells. Finally the function of these various proteins in relation with respect to their capacity to modulate immune response will be mechanistically examined again in cell- and exosome-based interactions.Several state-of-the-art approaches (including modified (pseudotyped) virions, isolation and analyses of exosomes, RNA interference-based RNA molecules and CRISPR) will be used in this study to understand the implication of these retrovirus-related proteins in the various roles that are attributed to trophoblasts and myoblast. The current research program will provide important new skills, knowledge and expertise that will be valuable toward implicated HQP for their future research career.The impact of our research will be important as our original approaches will shed a new light on how these hERV genes are turned on in and how they affect two different important biological processes and impact on their functions.