Grant: Discovery Grants Program - Individual

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.