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Dependent Traits in Mice Models of Hyperthyroidism and Hypothyroidism

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Dependent Traits in Mice Models of Hyperthyroidism and Hypothyroidism Phenotypical characterization of sex- dependent traits in mice models of hyperthyroidism and hypothyroidism Inaugural-Dissertation zur Erlangung des Doktorgrades Dr. rer. nat. der Fakultät für Biologie an der Universität Duisburg-Essen vorgelegt von Helena Rakov aus St. Petropawlowsk April 2017 Die der vorliegenden Arbeit zugrunde liegenden Experimente wurden am Universitätsklinikum Essen in der Klinik für Endokrinologie und Stoffwechselerkrankungen durchgeführt. 1. Gutachter: Prof. Dr. Dr. Dagmar Führer-Sakel 2. Gutachter: Prof. Dr. Elke Cario Vorsitzender des Prüfungsausschusses: Prof. Dr. Ruth Grümmer Tag der mündlichen Prüfung: 17.07.2017 Publications Publications Engels Kathrin*, Rakov Helena *, Zwanziger Denise, Moeller Lars C., Homuth Georg, Köhrle Josef, Brix Klaudia, Fuhrer Dagmar. Differences in mouse hepatic thyroid hormone transporter expression with age and hyperthyroidism. Eur Thyroid J 2015;4(suppl 1):81–86. DOI: 10.1159/000381020. *contributed equally Zwanziger Denise*, Rakov Helena*, Engels Kathrin, Moeller Lars C., Fuhrer Dagmar. Sex-dependent claudin-1 expression in liver of eu- and hypothyroid mice. Eur Thyroid J. 2015 Sep; 4(Suppl 1): 67–73. DOI: 10.1159/000431316. *contributed equally Engels Kathrin*, Rakov Helena*, Zwanziger Denise, Hoenes Georg Sebastian, Rehders Maren, Brix Klaudia, Koehrle Josef, Moeller Lars Christian, Fuhrer Dagmar. Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice. Endocrine. 2016 Oct;54(1):47-54. DOI: 10.1007/s12020-016-1020-8. Rakov Helena*, Engels Kathrin*, Hönes Georg Sebastian, Strucksberg Karl-Heinz, Moeller Lars Christian, Köhrle Josef, Zwanziger Denise, Führer Dagmar. Sex-specific phenotypes of hyperthyroidism and hypothyroidism in mice. Biol Sex Differ. 2016 Aug 24;7(1):36. DOI: 10.1186/s13293-016-0089-3. *contributed equally Rakov Helena*, Engels Kathrin*, Hönes Georg Sebastian, Brix Klaudia, Köhrle Josef, Moeller Lars Christian, Zwanziger Denise, Führer Dagmar. Influence of age on sex- specific phenotypical traits of thyroid dysfunctions. Submitted to Biology of Sex Differences. *contributed equally Rakov Helena, Hoenes Georg Sebastian, Möller Lars Christian, Führer Dagmar, Zwanziger Denise. Bile acid homeostasis in hypothyroid mice is exerted via water transport and tightening proteins. Submitted to The Journal of Lipid Research. Hönes Georg Sebastian, Rakov Helena, Logan John, Liao Xiao-Hui, Werbenko Eugenie, Pollard Andrea S., Rijntjes Eddy, Latteyer Sören, Engels Kathrin, Strucksberg Karl-Heinz, Zwanziger Denise, Klein-Hitpass Ludger, Köhrle Josef, Bassett J H Duncan, Williams Graham R., Refetoff Samuel, Führer Dagmar, Moeller Lars C.. Non-canonical thyroid hormone signalling mediates cardiometabolic effects in vivo. Submitted to Journal of Clinical Investigation. 3 Congress contributions Congress contributions Rakov H, Engels K, Zwanziger D, Renders M, Brix K, Hoenes S, Moeller LC, Führer D (2013). Molecular mechanisms of sex-dependent thyroid hormone action on target tissues. 12. Tag der Forschung der Medizinischen Fakultät, 23.11.2013, Universität Duisburg-Essen, poster presentation Rakov H (2013). Molecular mechanisms of gender-dependent thyroid hormone action on target tissues. 29th Arbeitstagung Experimentelle Schilddrüsenforschung, 12-14.12.2013, Essen, oral presentation Rakov H, Engels K, Zwanziger D, Renders M, Brix K, Hoenes S, Moeller LC, Führer D (2014). Molecular mechanisms of sex-dependent thyroid hormone action on target tissues. 57th Deutscher Kongress für Endokrinologie, 19-22.03.2014, Dresden, poster presentation Rakov H, Engels K (2014). Molecular mechanisms of age- and gender-dependent thyroid hormone action in target tissues. 2nd Annual Meeting of Thyroid Trans Act, 11-12.04.2014, Essen, joint oral presentation Rakov H (2014). Molecular mechanisms of gender-dependent thyroid hormone action on target tissues. BIOME Retreat (Genetics and Cell Biology core), 09- 10.07.2014, Mülheim an der Ruhr, oral presentation Rakov H, Engels K, Zwanziger D, Renders M, Brix K, Hoenes S, Moeller LC, Führer D (2014). Molecular mechanisms of sex-dependent thyroid hormone action on target tissues. ESE Bregenz Summer School, 03-07.08.2014, Bregenz, Swiss, poster presentation Rakov H, Engels K, Zwanziger D, Jaeger A, Rehn S, Rehders M, Brix K, Hoenes S, Moeller LC, Führer D (2014). Molecular mechanisms of sex-dependent thyroid hormone action on target tissues. 38th Annual Meeting of the ETA, 06-10.09.2014, Santiago de Compostela, Spain, poster presentation Rakov H, Engels K, Zwanziger D, Rehders M, Brix K, Hoenes S, Moeller LC, Führer D (2014). Molecular mechanisms of sex-dependent thyroid hormone action on target 4 Congress contributions tissues. 13. Tag der Forschung der Medizinischen Fakultät, 21.11.2014, Universität Duisburg-Essen, poster presentation Rakov H (2014). Influence of sex on thyroid hormone action in mice. 30th Arbeitstagung Experimentelle Schilddrüsenforschung, 04-05.12.2014, Bremen, oral presentation Rakov H, Engels K, Zwanziger D, Brix K, Koehrle J, Hoenes S, Moeller LC, Fuehrer D (2014). Gender aspects of hyperthyroidism and TH action in C57BL/6N mice. 1st Thyroid Trans Act International Conference, 05-07.12.2014, Bremen, poster presentation Rakov H, Engels K, Zwanziger D, Jaeger A, Rehn S, Hoenes S, Moeller LC, Führer D (2015). Thyroid hormone influence on lipid metabolism in brown adipose tissue and liver of male and female mice. 14. Tag der Forschung der Medizinischen Fakultät, 20.11.2015, Universität Duisburg-Essen, poster presentation Rakov H (2015). Impact of aging on lipid metabolism under TH dysfunction. 31st Arbeitstagung Experimentelle Schilddrüsenforschung, 10-12.12.2015, Berlin, oral presentation Rakov H, Engels K, Zwanziger D, Hoenes S, Moeller LC, Führer D (2016). Thyroid hormone influence on lipid metabolism of male and female mice. D.A.CH Tagung, 28-31.05.2016, München, poster presentation, flash talk Rakov H (2016). Molecular mechanisms of sex-dependent thyroid hormone action on target tissues. 4th Annual Meeting of Thyroid Trans Act, 10-11.06.2016, Essen, oral presentation Rakov H, Engels K, Zwanziger D, Hoenes S, Moeller LC, Führer D (2016). Influence of sex hormones on thyroid dysfunction. 15. Tag der Forschung der Medizinischen Fakultät 18.11.2016, Universität Duisburg-Essen, poster presentation 5 Congress contributions Rakov H, Engels K, Golchert J, Homuth G, Völker U, Hönes GS, Moeller LC, Rijntjes E, Köhrle J, Zwanziger D, Führer D (2017). Influence of age and thyroid hormones on liver transcriptome and lipid metabolism. 60th Deutscher Kongress für Endokrinologie, 15-17.03.2017, Würzburg, oral presentation Awards Rakov H, Engels K, Zwanziger D, Hoenes S, Moeller LC, Führer D (2016). Thyroid hormone influence on lipid metabolism of male and female mice. D.A.CH Tagung, 28-31.05.2016, München, poster award and flash talk 6 Zusammenfassung Zusammenfassung Schon lange ist eine erhöhte Prävalenz von Frauen für Schilddrüsen- (SD) Funktionsstörungen wie einer Über- oder Unterfunktion bekannt. Allerdings sind die Auswirkungen einer SD-Fehlfunktion im menschlichen Organismus kaum geschlechtsspezifisch charakterisiert. Zudem steigt die Rate an SD- Funktionsstörungen mit dem Alter an und auch hierbei ist bislang nur unzureichend bekannt, ob eine Über- oder Unterfunktion bei älteren Frauen im Vergleich zu Männern ähnliche Konsequenzen hat im Hinblick auf z.B. das kardiovaskuläre System, den Energiestoffwechsel oder das Verhalten. Um diese klinischen Fragestellungen in einem in vivo Mausmodell nachzustellen, wurden zunächst Protokolle für eine chronische Überfunktion in männlichen und weiblichen Tieren etabliert. Im Anschluss erfolgte eine Charakterisierung von geschlechtsspezifischen Eigenschaften einer Über- und Unterfunktion in verschiedenen Lebensabschnitten bei jungen, erwachsenen und alten Mäusen sowie Analysen zur organspezifischen SD-Hormon (SDH) Wirkung. Im Vergleich der jungen Tiere zeigte sich, dass das Geschlecht eine wichtige Rolle bei SDH-abhängigen Veränderungen des Körpergewichts, der Körpertemperatur, der Futter- und Wasseraufnahme, den SDH-Serumkonzentrationen und neuro- muskulären Eigenschaften spielt. Im Vergleich von erwachsenen und älteren Tieren wurde sowohl eine gleichbleibende (für Körpertemperatur, SDH-Serum- konzentrationen, Aktivität) als auch verstärkte (für Körpergewicht, Muskelfunktion) geschlechtsabhängige SDH-Wirkung beobachtet. Interessanterweise ließen sich in allen drei Altersgruppen keine Unterschiede zwischen Männchen und Weibchen in der Herzfrequenz bei einer Über- und Unterfunktion beobachten. In der Analyse der organspezifischen SDH-Wirkung zeigte sich, dass die SDH-abhängige Genexpression im Herzen die geringsten geschlechtsspezifischen Unterschiede aufweist, während im braunen Fettgewebe und noch deutlicher in der Leber ausgeprägte geschlechts- und SDH-spezifische Transkriptänderungen auftraten. In weiteren Analysen konnte eine geschlechts- und SDH-abhängige Regulation von Claudin-1 in der Leber nachgewiesen werden, welche wahrscheinlich eine Relevanz für die Gallensäure Homeostase hat und einen möglichen Pathomechanismus für geschlechtsabhängige Cholelithiasis bei SD-Funktionsstörungen darstellen könnte. 7 Zusammenfassung Zusammenfassend sind dies die ersten Arbeiten, welche geschlechtsspezifische Aspekte einer SD-Über- oder Unterfunktion in verschiedenen Lebensaltern im Mausmodell abbilden. Diese Ergebnisse dienen als Grundlage, um die molekularen Mechanismen auf organischer und Zellebene zu verstehen. Dies kann helfen, translational zukünftig am Menschen
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