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

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    Sujet thèse R. Andriantsitohaina

    Sujet thèse R. Andriantsitohaina

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    Extracellular Vesicle-borne Protein tyrosine phosphatase 1B and Inflammation in Metabolic syndrome

    Supervisor: Andriantsitohaina Ramaroson

    Phone number: +33 2 44 68 85 80

    Email address: ramaroson.andriantsitohaina @ univ-angers.fr

    Socio-economic and scientific context:

    Obesity and its metabolic resultant dysfunctions such as insulin resistance, hyperglycemia, dyslipidemia and hypertension, grouped as the “Metabolic Syndrome” (MetS), are chronic inflammatory disorders that represent one of the most severe epidemic health problems. MetS is characterised by a low-grade inflammatory state and by endocrine changes. The low-grade inflammatory state leads to loss of lean body mass, reduced immune function, cognitive decline, accelerated atherosclerosis and insulin resistance that lead to the increase of cardiovascular diseases (CVD) and type 2 diabetes (T2DM). Novel strategy is needed to fight against the CDV consequences of obesity and its metabolic consequences. Our group have described that circulating extracellular vesicles (EVs), including microvesicles (MVs) and Exosomes (EXOs), small vesicles released from activated or apoptotic cells, are increased in patients from MetS including pro-coagulant and pro-inflammatory EVs, and mainly those from platelets, endothelial cells and erythrocytes. Moreover, we found that both MVs and EXOs of MetS participate in endothelial dysfunction, vascular hyporeactivity and vascular remodeling leading to atherosclerosis. We have found that hepatic-specific deletion of protein tyrosine phosphatase 1B (PTP1B), in addition to improving glucose and lipid homoeostasis and increasing insulin sensitivity, was protective against endothelial dysfunction in response to high fat diet (HFD). Thus, inhibition of PTP1B might have therapeutic potential in treatment of CVD and atherosclerosis.

    Working hypothesis and aims:

    Our preliminary results indicate that circulating EVs bear PTP1B (EVPTP1B+) (see preliminary data). Of importance is that PTP1B is expressed in circulating EXO but not in MV patients and its expression is highly expressed in MetS compared to non-MetS patients. EVs from MetS patients, in addition to represent predictive factors, may account for specific inflammatory complications increasing the occurrence of diabetes described in MetS. The objective of the present project is to test the hypothesis that PTP1B carried by EVs (EVsPTP1B+) from MetS patients may be responsible, at least in part, to the enhanced inflammatory process that alter angiocrine repertoire of macrophages and adipocytes leading to vascular remodeling described in atherosclerotic patients and to MetS-associated insulin-resistance and T2DM. We hypothesize that silencing/inhibiting PTP1B in these EVs will have insulin sensitizing effects at the whole body level and will test this directly using the unique genetic and pharmacological tools available in our laboratories.

    Main milestones of the thesis:

    - Detection, characterization and sorting subsets isolations of EVs and especially EVsPTP1B+ in plasma of MetS and non-MetS patients. The size and the concentration of EVs from each patient will be analyzed by transmission electronic microscopy, Western blot, Nanoparticle tracking Analysis (NTA) and flow cytometry.

    - Validation of the implication of EVsPTP1B+ in inflammatory response of monocyte/macrophages and adipocytes and their pathophysiological relevance in the course of atherosclerosis. The effects of EV subtypes will be analyzed on monocyte/macrophage phenotypes and function with respect to cytokine releases and on adipocytes. The influence of EVs on adipocyte differentiation and to go further into mechanistic action of EVs on adipokine regulation from preadipocytes from human adipose tissues will be determined. Transcriptomic analysis of adipocytes treated by EVs from patients will be conducted in order to elucidate the mechanisms and molecular targets involved. In vivo effects of EVs will be tested in animal models for the pathophysiological relevance of EVs with special interest in using LysM-PTP1B mice ((lacking PTP1B specifically in the myeloid lineage).

    - Correlations between EVsPTP1B+ of non-MetS and MetS patients from the NUMEVOX cohort with clinical parameters and biological data will be analyzed. Of particular interest is the correlation with individual risk factors such as hypertension, diabetes, hypercholesterolemia in relation with atherosclerosis. The same correlations will be undertaken in mice models

    Scientific and technical skills required by the candidate:

    - Cellular Biology, Molecular biology, Imaging and functional studies of vascular function in mice