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，一些DNA区域保留了产生病毒的能力，尽管这些病毒不具有感染性，但可以在细胞外环境中观察到。这些病毒被称为人内源性逆转录病毒（hERV）。人类生物体中hERV的存在很少与生物学现象相关，尽管称为合胞素-1、合胞素-2、EnvK和EnvP（B）的四种hERV蛋白代表古老逆转录病毒的包膜蛋白，可能对胎盘和/或骨骼肌的发育很重要。有趣的是，小鼠ERV（mERV）包膜蛋白的等价物，称为Syncytin-A和Syncytin-B，已被鉴定并被认为也参与了小鼠胎盘和骨骼肌的发育/形成。我们的短期目标是通过研究这些蛋白质在滋养层（胎盘衍生细胞）和成肌细胞（肌肉细胞）中表达的调节机制，具体检查这些蛋白质在人/小鼠胎盘发育和骨骼肌形成中的参与。不同的调节机制正在探索中，并基于我们实验室的初步结果和以前对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介导其功能，以及这些相互作用如何受到其他细胞蛋白质的影响。 这些相互作用将在两种不同细胞之间相互作用的背景下进行研究，但也在称为外泌体的循环微球与靶细胞之间相互作用的背景下进行研究。 最后，将在基于细胞和外泌体的相互作用中再次机械地检查这些不同蛋白质的功能与它们调节免疫应答的能力的关系。（包括修饰的（假型化的）病毒体，外来体的分离和分析，基于RNA干扰的RNA分子和CRISPR）将用于本研究，以了解这些逆转录病毒的含义。相关蛋白质在滋养层和成肌细胞中发挥各种作用。目前的研究计划将提供重要的新技能，知识和专业知识，这将是有价值的牵连HQP为他们未来的研究生涯，我们的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基因是如何打开，以及它们如何影响两个不同的重要生物过程和影响他们的功能的新的光。

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.