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Étude Omique De La Régulation De La Thyroïde Par L'iode Et Du Rôle De

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Étude Omique De La Régulation De La Thyroïde Par L'iode Et Du Rôle De Étude omique de la régulation de la thyroïde par l’iode et du rôle de SLC5A8 dans la thyroïde Maha Hichri To cite this version: Maha Hichri. Étude omique de la régulation de la thyroïde par l’iode et du rôle de SLC5A8 dans la thyroïde. Médecine humaine et pathologie. COMUE Université Côte d’Azur (2015 - 2019), 2018. Français. NNT : 2018AZUR4061. tel-02101065 HAL Id: tel-02101065 https://tel.archives-ouvertes.fr/tel-02101065 Submitted on 16 Apr 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE DE DOCTORAT Étude omique de la régulation de la thyroïde par l’iode et du rôle de SLC5A8 dans la thyroïde Maha HICHRI TIRO-MATOs UMR E4320 Présentée en vue de l’obtention Devant le jury, composé de : du grade de docteur en Sciences de la vie Anne-Sophie Gay, IR, CNRS et de la Santé Luc Camoin, IR (HDR), Inserm Mention : Interactions moléculaires et Laurent Counillon, PR, UNS cellulaires Sylvie Chevillard, DR, CEA d’Université Côte d’Azur Dirigée par : Thierry Pourcher Co-encadrée par : Sabine Lindenthal Soutenue le : 23 Novembre 2018 Université Côte d’azur École Doctorale des Sciences de la Vie et de La Santé (ED85) Thèse de doctorat Présentée par Maha Hichri Étude omique de la régulation de la thyroïde par l’iode et du rôle de SLC5A8 dans la thyroïde Devant le jury composé de : Président de jury Pr. Laurent Counillon, Professeur 1, UNS LP2M - CNRS-UNS UMR 7370 Université de Nice-Sophia Antipolis Rapporteurs Dr. Luc Camoin, Ingénieur de recherche, INSERM Institut de cancérologie et d’immunologie de Marseille INSERM U1068 -CNRS UMR7258 -Aix-Marseille Université Dr. Sylvie Chevillard, Directeur de recherche, CEA LCE_ Laboratoire de Cancérologie expérimentale CEA/DVS/IRCM/SRETT - CEA Fontenay-aux-Roses Examinateur Dr. Anne-Sophie Gay, Ingénieur de recherche, CNRS Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) UMR7275 CNRS et Université de Nice Sophia Antipolis Directeur de thèse Dr, Thierry Pourcher, Directeur de recherche, CEA TIRO-MATOs, UMR E4320 Étude omique de la régulation de la thyroïde par l’iode et du rôle de SLC5A8 dans la thyroïde Résumé L’iode est un composant essentiel aux hormones thyroïdiennes. Les cellules thyroïdiennes captent l’iode circulant et le concentrent vers le colloïde. Il est alors incorporé à la thyroglobuline, protéine précurseur des hormones, par un mécanisme d’organification. La capacité de captation de l’iode par la thyroïde est finement régulée notamment par la « Thyroid Stimulating Hormone » (TSH) mais aussi l’iode circulant. En effet, en cas d’une élévation de l’iode circulant, la thyroïde déclenche un mécanisme de régulation appelée l’effet Wolff- Chaikoff. Ce phénomène se traduit par une limitation transitoire de production des hormones thyroïdiennes qui s’accompagne notamment d’une diminution de l’expression du NIS (Natrium Iodide Symporter), la protéine responsable du transport actif de l’iode dans la thyroïde. Dans cette étude, des approches omiques globales ont été mises à profit pour étudier cette régulation dans le contexte de l’administration d’un produit iodé et de souris invalidées pour un gène codant pour un transporteur de monocarboxylate exprimé dans la thyroïde. Dans la première partie de ce travail, l’effet des agents de contraste iodés (ICA), couramment utilisés en imagerie médicale, a été étudié. L’administration de ces agents entraine une réduction de la captation de l’iode souvent expliquée par un effet Wolff-Chaikoff associé à un potentiel relargage d’iode. Par une approche de protéomique quantitative global, le protéome de thyroïde de souris, après administration d’ICA, a été comparé au protéome après administration d’iode. Après un traitement des données et une analyse bioinformatique, nos résultats mettent en évidence l’existence de peu de mécanismes en commun induits par l’iode et les ICA mais cependant de plus importantes variations d’expression de protéines sont déclenchées uniquement par les ICA. Dans la deuxième partie, le rôle de SLC5A8 dans la fonction thyroïdienne et les mécanismes sous-jacents à l’effet Wolff-Chaikoff ont été étudiés chez des souris invalidées pour le gène Slc5a8 (Solute carrier family 5 number 8) et des souris non mutées. SLC5A8 est une protéine membranaire identifiée au laboratoire et exprimée dans la membrane apicale du thyrocyte. Cette protéine catalyse un transport de monocarboxylate dans différents organes mais son rôle dans la thyroïde demeure non élucidé. L’invalidation n’entraine pas d’effet majeur sur la fonction thyroïdienne. En mettant à profit une approche multiomique comparative, combinant la transcriptomique, la protéomique et la métabolomique, les effets de cette invalidation combinée ou non à une administration d’iode ont été explorés. Le traitement des data révèle de nombreuses voies activées dans les différentes conditions avec des effets inverses à ceux de l’invalidation par l’administration d’iode. L’ensemble des résultats indiquent que la perte de fonction de SLC5A8 affecte l’organification de la thyroglobuline et le contrôle du stress oxydatif. Mots Clefs : Thyroïde, Wolff-Chaikoff, agent de contraste, SLC5A8, protéomique quantitative Multiomics study of thyroid regulation by iodide and the role of SLC5A8 in the thyroid Abstract Iodine is an essential component of thyroid hormones. Thyroid cells trap the circulating iodide and accumulate it in the colloid. Iodide is subsequently organified and incorporated into the thyroglobulin, the hormone precursor protein. The iodide uptake capacity of the thyroid is finely regulated, not only by the Thyroid Stimulating Hormone (TSH), but also by the levels of circulating iodide. Indeed, an increase in the blood iodide concentration evokes a regulating mechanism called the Wolff-Chaikoff effect. This phenomenon includes a transient inhibition of thyroid hormone release and a decrease in the expression of NIS (Natrium Iodide Symporter), the protein that mediates the active transport of iodide in the thyroid.Here, global “omics” approaches were used to study this regulation after administration of iodide or iodinated contrast agents in wild-type mice and mice that were deficient for the monocarboxylate transporter (SLC5A8). In the first part of this study, we analyzed the effect of iodinated contrast media (ICM; commonly used in medical imaging). The administration of these agents leads to a reduction in the uptake of iodide, which is often explained by the Wolff-Chaikoff effect associated with a putative iodine release from the compound. Using a quantitative proteomic approach, the mouse thyroid proteome, was assessed before and after the administration of of ICM or iodide. In the second part, the role of SLC5A8 in thyroid function and the molecular mechanisms underlying the Wolff-Chaikoff effect were studied in both SLC5A8-deficient and wild type mice. SLC5A8 is a membrane protein that is expressed in the apical membrane of thyrocytes. This protein mediates monocarboxylate transport in different organs but its role in the thyroid remains unsolved. SLC5A8-deficient mice have no apparent thyroid dysfunction, but some preliminary result have shown that SLC5A8-deficient mice have impaired iodide-mediated regulation of the thyroid. Using a multiomic approach that combines transcriptomics, proteomics and metabolomics, the effect of the lack of SLC5A8 was studied I, terms of thyroid function and thyroid rregulation by iodide. Data processing revealed several activated pathways. Our results indicate that SLC5A8 function is important for organification of thyroglobulin, and control of oxidative stress. Keywords: Thyroid, Wolff-Chaikoff, Iodinated Contrast Media, SLC5A8, quantitative proteomics Table des matières Liste des figures___________________________________________________________________ 3 Liste des tableaux _________________________________________________________________ 5 Liste des annexes __________________________________________________________________ 6 Liste des abréviations ______________________________________________________________ 7 Partie 1 : Rapport Bibliographique __________________________________________________ 9 Chapitre 1 : La fonction thyroïdienne _____________________________________________ 10 I. L’importance de l’iode dans la thyroïde _________________________________________ 10 II. La thyroïde _______________________________________________________________ 12 II.1. Organogénèse de la glande thyroïde ________________________________________ 13 III. La synthèse des hormones thyroïdiennes ______________________________________ 13 III.1. Mécanismes de transport de l’iode _______________________________________ 14 III.2. Mécanismes de l’organification _________________________________________ 15 IV. La régulation de la fonction thyroïdienne par la thyrotropine (TSH) _________________ 18 V. La régulation de la fonction thyroïdienne par l’iode ______________________________ 21 Chapitre 2 : L’effet Wolff Chaikoff et ses applications _______________________________ 25 I. L’effet Wolff-Chaikoff et son application en radioprotection _________________________ 25 II.
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