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INSERM UMR 1063 : Stress oxydant et pathologies métaboliques (SOPAM)

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    Sujet thèse R. Andriantsitohaina et J. Bursier

    Sujet thèse R. Andriantsitohaina et J. Bursier

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    Contribution of extracellular vesicles from microbiota in the pathophysiology of liver diseases: nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

    Context: Extracellular vesicles (EVs) including microparticles and exosomes are released by cells and contain lipids, proteins and nucleic acids, such as DNA, protein coding, and non-coding RNAs. Owing to their composition, EVs can (i) activate receptors at the target cell and then, the subsequent intracellular pathway associated to the specific receptor; (ii) transfer molecules to the target cells and thereby change their phenotype and (iii) be used as shuttle to carry specific molecules towards specific cells. During the last years, it has been evidenced the importance of the control of the balance between the different subsets of microbiota in the digestive tract in the development of chronic diseases affecting different barriers functions. Recent reports show that the communication between host and microbiota is bidirectional thus gut bacteria can release EVs and modify host metabolic homeostasis. On the other hand, gut epithelial cells produce EVs that can affect microbiome. The accumulation of triglycerides into hepatocytes observed during obesity and metabolic syndrome (MetS) results in liver steatosis, called to as nonalcoholic fatty liver disease (NAFLD). Some NAFLD patients develops nonalcoholic steatohepatitis (NASH), characterized by hepatic inflammation, fibrosis, and cirrhosis. EVs have been implicated in the process leading to liver diseases, but no data have been reported with regards to EVs microbiota.

    Objective: The aim of the present project is to evaluate the contribution of EVs, microparticles and exosomes from microbiota, in MetS and liver diseases patients affecting endothelial barriers leading to liver diseases. Special interest will be taken to oxidative stress, inflammation and defect in tissue functions. First, we will isolate EVs from microbiota and from endothelial cells in response to either to microbiota or inflammatory process. EV “omic” studies will be conducted to analyze proteins and their post-translational modifications (phosphorylation), noncoding RNAs (miRNAs and lncRNAs). The effects of EV of interest will be analyzed in endothelial cells and hepatocytes. Key cellular processes like adhesion, apoptosis, proliferation, migration, permeability, oxidative and nitrative stresses, lipid accumulation and inflammation will be determined. These analyses will generate new data on EV and their impact on key processes involved in barrier dysfunction. Three approaches will be used: pharmacological, biochemical and molecular approaches. Also, longitudinal approaches will be conducted from cellular, pre-clinical with animal models of disease interest and clinical data from already well-established cohorts of MetS and SNIFF.

    The proposed project is by nature a project anchored on translational biomedicine, making a bridge between the clinic and the laboratory. Thus, the project will follow a path as informed by pathology and human disease, into mechanisms and integrated in vivo systems, making its deliverables more likely amenable to rapid translation and development for clinical application. They will also help for a better knowledge on EVs as both biological vector of information of diseases associated with barrier dysfunction and potential biomarkers.