Regulation of expression and functions of endogenous retrovirus envelope proteins

内源逆转录病毒包膜蛋白表达和功能的调节

• 批准号: RGPIN-2018-06206
• 负责人: Barbeau, Benoit
• 金额: $ 3.06万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765188
• 关键词: Regulation; expression; functions; endogenous; retrovirus

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.

人类基因组具有序列，该序列源自称为逆转录病毒的病毒，并整合了数百万年前的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，但据报道有些DNA区域保留了生成病毒的能力，尽管非感染，但在细胞外环境中可以观察到。这些病毒被称为人内源性逆转录病毒（HERV）。人类有机体中HERV的存在很少与生物学现象相关，尽管代表古代逆转录病毒包膜蛋白的四种称为Syncytin-1，Syncytin-2，Envk和Envp（b）的HERV蛋白可能对开发的逆转录病毒的包膜蛋白可能很重要胎盘和/或骨骼肌。有趣的是，已经确定并建议等效的小鼠ERV（MERV）包膜蛋白称为合成蛋白A和Syncytin-B，也建议还参与鼠胎盘和骨骼肌的发育/形成。我们的长期目标是更好地理解调节模式和ERV信封在不同生物学过程中的功能，更确切地说，在此提案中，我们的短期目标是通过研究这些蛋白质在人/小鼠胎盘发育中的参与和骨骼肌形成。其在滋养细胞（胎盘衍生的细胞）和成肌细胞（肌肉细胞）中调节其表达的机理。正在探索不同的调节机制，并基于我们实验室和先前关于HIV-1的研究的初步结果。我们还将研究这些蛋白如何通过与受体相互作用以及这些相互作用如何受其他细胞蛋白的贡献来介导其功能。 这些相互作用将在两个不同细胞之间的相互作用的背景下进行研究，也将在被称为外泌体与靶细胞的循环脂质球之间的相互作用。 最后，这些各种蛋白质相对于它们调节免疫反应的能力的功能将在基于细胞和外部的相互作用中再次进行机械检查。几个最新的方法（包括修改（假型）病毒粒子，分离，分离在本研究中，将使用外泌体，基于RNA干扰的RNA分子和CRISPR的分析，以了解这些逆转录病毒相关蛋白在各种作用中的含义，这归因于滋养细胞和成肌细胞。当前的研究计划将提供重要的新技能，知识和专业知识，这些技能和专业知识将有价值地参与HQP的未来研究职业。我们的研究的影响将很重要，因为我们的原始方法将对这些HERV基因的转化方式发出新的启示在IN以及它们如何影响两个不同的重要生物学过程并影响其功能。