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Etude du rôle de facteurs génétiques et épigénétiques dans l'homéostasie et la fonction des cellules pancréatiques

Abstract : The pancreas is crucial for food digestion and glycemic control. Its functional diversity is based on transcriptional and epigenetic factors which ensure the regulation of cellular identity and function. My thesis aims to characterize the role of some of these factors. We previously showed that Hnf1b is required for pancreas development. We show here that Hnf1b post-natal inactivation in mouse leads to strong ductal defects and pancreatitis associated with intraepithelial neoplasia. In human, HNF1B heterozygous mutations cause the MODY5 pathology. We analyzed a unique MODY5 mouse model generated by insertion of human mutation in mouse. We show that these mice constitute a valuable model of the disease. They are glucose intolerant and display reduced total volume of large islets and beta-cells. The exocrine compartment is also altered as mice develop a pancreatitis phenotype. Our analyses suggest an embryonic etiology. Previously, our team revealed HDAC roles in pancreas development. Pancreas regeneration and pancreas development sharing common molecular pathways, we investigated the role of HDACs in pancreas regeneration. We found that HDAC3 inactivation sensitizes acinar tissue to inflammation and prevents its regeneration. Our studies reveal new molecular mechanisms implied in the development of pancreatitis, pancreatic cancer and diabetes. These data could contribute to the identification of new therapeutic targets for the treatment of pancreatic pathologies.
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Submitted on : Tuesday, October 1, 2019 - 1:03:10 AM
Last modification on : Thursday, December 10, 2020 - 11:06:10 AM


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Evans Quilichini. Etude du rôle de facteurs génétiques et épigénétiques dans l'homéostasie et la fonction des cellules pancréatiques. Biologie cellulaire. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066219⟩. ⟨tel-02301988⟩



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