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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=644609
• 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.***

人类基因组中包含一些序列，这些序列源于逆转录病毒，并在数百万年前整合了灵长类动物的基因组。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。这些病毒称为人内源性逆转录病毒（hERV）。hERV在人类机体中的存在很少与生物现象相关，尽管代表古代逆转录病毒包膜蛋白的四种hERV蛋白（Syncytin-1、Syncytin-2、EnvK和EnvP(b)）可能对胎盘和/或骨骼肌的发育很重要。有趣的是，等效的小鼠ERV （mERV）包膜蛋白，称为Syncytin-A和Syncytin-B，已被确定并提示也参与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包膜在不同生物过程中的调节模式和功能，更准确地说，在本提案中，我们的短期目标是通过研究这些蛋白在滋养细胞（胎盘源细胞）和成肌细胞（肌肉细胞）中的表达调节机制，专门研究这些蛋白在人/小鼠胎盘发育和骨骼肌形成中的作用。基于我们实验室的初步结果和先前对HIV-1的研究，正在探索不同的调节机制。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它们的功能，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，也将在循环脂质球体（称为外泌体）与靶细胞之间相互作用的背景下进行研究。最后，在细胞和外泌体相互作用中，这些不同蛋白质的功能及其调节免疫反应的能力将再次进行机械检查。****本研究将使用几种最先进的方法（包括修饰（伪型）病毒粒子、外泌体的分离和分析、基于RNA干扰的RNA分子和CRISPR）来了解这些逆转录病毒相关蛋白在滋养层细胞和成肌细胞的各种作用中的含义。目前的研究计划将提供重要的新技能，知识和专业知识，这将对牵连HQP未来的研究生涯有价值。****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基因是如何开启的，以及它们如何影响两个不同的重要生物过程及其功能。***