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Einfluss Des Diabetes Mellitus Typ 2 Assoziierten Gens CDKAL1 Auf Die Endokrine Funktion Pankreatischer Betazellen

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Einfluss Des Diabetes Mellitus Typ 2 Assoziierten Gens CDKAL1 Auf Die Endokrine Funktion Pankreatischer Betazellen View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Qucosa - Publikationsserver der Universität Leipzig Einfluss des Diabetes mellitus Typ 2 assoziierten Gens CDKAL1 auf die endokrine Funktion pankreatischer Betazellen Dissertation zur Erlangung des akademischen Grades Dr. med. an der Medizinischen Fakultät der Universität Leipzig eingereicht von: Manuel Mai geboren am 29.06.1986 in Leipzig angefertigt an der Klinik für Gastroenterologie, Universitätsklinikum Leipzig Betreuer: Prof. Dr. med. A. Hoffmeister Beschluss über die Verleihung des Doktorgrades vom: 16.04.2019 Inhaltsverzeichnis Inhaltsverzeichnis INHALTSVERZEICHNIS ............................................................................................... 2 ABKÜRZUNGSVERZEICHNIS ...................................................................................... 4 1 EINFÜHRUNG UND AUFGABENSTELLUNG .......................................................... 5 1.1 DIABETES MELLITUS ................................................................................................ 5 1.2 INSULIN ................................................................................................................ 6 1.3 RNA-INTERFERENZ ................................................................................................ 7 1.4 CDKAL1: CDK5 REGULATORY SUBUNIT ASSOCIATED PROTEIN 1-LIKE 1 ............................ 9 1.4.1 Entdeckung von CDKAL1 ............................................................................... 9 1.4.2 CDK5 (cyclin-dependent kinase 5) und p35 ................................................. 10 1.4.3 Rolle des CDKAL1 in der Pathogenese des Diabetes mellitus ..................... 11 1.5 FRAGESTELLUNG .................................................................................................. 12 2 MATERIALIEN UND METHODEN ...................................................................... 13 2.1 GERÄTE .............................................................................................................. 13 2.2 CHEMIKALIEN ...................................................................................................... 13 2.3 PCR-PRIMER ...................................................................................................... 14 2.4 ZELLKULTUR ........................................................................................................ 14 2.4.1 INS-1E Zellen ............................................................................................... 14 2.4.2 Zellkulturmedium ........................................................................................ 14 2.4.3 Zellkultivierung ............................................................................................ 15 2.5 TRANSFEKTION MIT SIRNA (SMALL INTERFERING RNA) ............................................... 15 2.6 STIMULATION UND PROBENGEWINNUNG .................................................................. 16 2.7 MOLEKULARBIOLOGIE ........................................................................................... 17 2.7.1 RNA-Extraktion............................................................................................ 17 2.7.2 RNA-Konzentrationsbestimmung ............................................................... 17 2.7.3 Reverse Transkription ................................................................................. 17 2.7.4 Quantitative Real-Time PCR ........................................................................ 17 2.7.5 Onestep PCR (Reverse Transkription und Real-Time PCR) .......................... 19 2.7.6 Auswertung der Real-Time PCR .................................................................. 20 2.8 INSULINKONZENTRATIONSBESTIMMUNG ................................................................... 20 2.9 GELELEKTROPHORESE ............................................................................................ 21 2 3 ERGEBNISSE .................................................................................................... 22 3.1 NACHWEIS VON CDKAL1 IN INS-1E ....................................................................... 22 3.2 REAL-TIME PCR ZUR QUANTITATIVEN ANALYSE ......................................................... 23 3.3 VOREXPERIMENTE ................................................................................................ 25 3.3.1 Evaluation der ausgesäten Zellzahl ............................................................ 25 3.3.2 Evaluation der Stimulationsdauer .............................................................. 26 3.4 CDKAL1-SUPPRIMIERUNG MITTELS RNA-INTERFERENZ .............................................. 27 3.5 STIMULATIONSEFFEKTE DURCH GLUKOSE UND KALIUMCHLORID .................................... 29 3.6 QUANTIFIZIERUNG DES INSULINPROTEINS .................................................................. 31 3.6.1 Extrazelluläre Insulinkonzentration ............................................................ 31 3.6.2 Intrazelluläre Insulinkonzentration ............................................................. 33 3.7 QUANTIFIZIERUNG DER INSULIN MRNA .................................................................... 35 3.7.1 Zellen ohne Stimulans ................................................................................. 35 3.7.2 Zellen mit Glukose-Stimulans ...................................................................... 36 3.7.3 Zellen mit Kaliumchlorid-Stimulans ............................................................ 38 4 DISKUSSION.................................................................................................... 39 ZUSAMMENFASSUNG ............................................................................................ 45 LITERATURVERZEICHNIS ......................................................................................... 47 TABELLEN- UND ABBILDUNGSVERZEICHNIS ............................................................ 51 ERKLÄRUNG ÜBER DIE EIGENSTÄNDIGE ABFASSUNG DER ARBEIT ........................... 52 LEBENSLAUF........................................................................................................... 53 PUBLIKATIONSLISTE ............................................................................................... 54 DANKSAGUNG ....................................................................................................... 55 3 Abkürzungsverzeichnis Abkürzungsverzeichnis ATP Adenosintriphosphat bp Basenpaare BSA bovines Serumalbumin CDK Cyclin-abhängige Kinase (cyclin-dependent kinase) CDK5RAP1 CDK5 regulatory subunit associated protein 1 CDKAL1 CDK5 regulatory subunit associated protein 1-like 1 cDNA complementary DNA DNA Desoxyribonukleinsäure (Deoxyribonucleic acid) dNTP Desoxyribonukleosidtriphosphate EDTA Ethylendiamintetraacetat ELISA Enzyme-linked Immunosorbent Assay FKS fötales Kälberserum HbA1c glykiertes Hämoglobin A1c HEPES N-2-Hydroxyethylpiperazin-N'-2-ethansulfonsäure HPRT Hypoxanthin-Guanin-Phosphoribosyltransferase KCl Kaliumchlorid kDa Kilodalton KRBH Krebs-Ringer-Bikarbonat-HEPES mM Millimolar (mmol/l) mRNA messenger RNA PBS phosphatgepufferte Kochsalzlösung (phosphat buffered saline) PCR Polymerasekettenreaktion (polymerase chain reaction) RNA Ribonukleinsäure (Ribonucleic acid) RISC RNA-induced silencing complex rpm Umdrehungen pro Minute (revolutions per minute) siRNA small interfering RNA SNP Single Nucleotide Polymorphism TAE Tris-Acetat-EDTA-Puffer tRNA transfer RNA VLE-RPMI very low endotoxine-Roswell Park Memorial Institute 4 Einführung und Aufgabenstellung 1 Einführung und Aufgabenstellung 1.1 Diabetes mellitus Diabetes mellitus ist eine Stoffwechselerkrankung, die zu einer chronisch erhöhten Glukosekonzentration im Blut führt (Hyperglykämie). Nach aktuellen Leitlinien der Deutschen Diabetes Gesellschaft werden verschiedene Typen unterschieden: Typ-1- Diabetes, Typ-2-Diabetes, der Gestationsdiabetes (welcher durch das erstmalige Auftreten in der Schwangerschaft gekennzeichnet ist), der durch genetische Defekte der Betazell-Funktion verursachte Diabetes und andere spezifische Typen, wie z.B. der pankreoprive oder medikamentös induzierte Diabetes mellitus (Nauck et al. 2017). Während es beim Diabetes mellitus Typ 1 zu einer meist immunologisch vermittelten Zerstörung der pankreatischen Betazellen und damit zu einem absoluten Insulinmangel kommt, steht beim Typ-2-Diabetes die Insulinresistenz mit einem relativen Insulinmangel im Vordergrund. So bedarf der Typ-1-Diabetes von Beginn an einer Insulintherapie, während bei der Insulinresistenz zunächst andere medikamentöse Optionen in Frage kommen. Zudem ist der Diabetes mellitus Typ 2 häufig mit anderen Begleiterscheinungen des sogenannten metabolischen Syndroms (z.B. Adipositas oder Bluthochdruck) assoziiert. Im Jahre 2017 waren weltweit 425 Millionen Menschen an Diabetes erkrankt (International Diabetes Federation 2017). Nach Angaben des Robert-Koch-Instituts zeigt sich in Deutschland eine Prävalenz des Diabetes mellitus der über 18-jährigen von 8,9 % (Lange 2014). Durch verbesserte Präventionsmaßnahmen und Behandlungsmöglichkeiten hat sich zwar die Überlebensdauer verbessert, die Prävalenz zeigt aber weiterhin eine steigende Tendenz. Dies ist vor allem durch die weltweit zunehmende Verbreitung der Risikofaktoren Bewegungsmangel, Fehlernährung und der damit einhergehenden Adipositas begründet (Kolb et al. 2010). Besonders aufgrund der spät symptomatisch auftretenden Folgeerscheinungen geht die Erkrankung mit
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