Publikationsserver der Universitätsbibliothek Marburg
Titel:Funktionelle Charakterisierung und Wirksamkeitsvergleich unterschiedlicher Varianten eines DNAzyms gegen den Transkriptionsfaktor GATA-3
Autor:Behrje, Johanna
Weitere Beteiligte: Garn, Holger (Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0156
URN: urn:nbn:de:hebis:04-z2013-01563
DOI: https://doi.org/10.17192/z2013.0156
DDC:610 Medizin
Titel (trans.):Functional Characterization and Comparative Effectiveness of Differently Modified Variants of a DNAzyme Directed Against the Transcription Factor GATA-3
Publikationsdatum:2013-04-22
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
GATA-3, Modifikation, DNAzyme, GATA-3, DNAzym, Immunsystem, Modification, Allergisches Asthma, Antisense-Oligonucleotide, Transkriptionsfaktor

Zusammenfassung:
Das allergische Asthma bronchiale ist eine chronische entzündliche Erkrankung der Atemwege, welche durch eine reversible Bronchoobstruktion, bronchiale Hyperreagibilität, Schleimhautödem und erhöhte Mukusproduktion gekennzeichnet ist. Innerhalb der Immunpathogenese einer allergischen Entzündungsreaktion spielt der Transkriptionsfaktor GATA-3 aufgrund seiner Funktion bei der Differenzierung und Aktivierung von Th2-Zellen und der Expression in Eosinophilen, Mastzellen und natürlichen Killer-T-Zellen eine zentrale Rolle und stellt aufgrund dessen ein interessantes therapeutisches Angriffsziel dar. Eine neue Therapiestrategie sind Antisense-Technologien. Sie bieten die Möglichkeit einer frühen therapeutischen Intervention, da sie direkt mit der mRNA der Zielmoleküle interagieren und so die spezifische Inhibierung der Expression eines Gens bewirken können. Zu den wichtigsten Antisense-Strategien gehören unter anderem DNAzyme, RNA-spaltende einzelsträngige Desoxyoligonukleotide. Durch die Möglichkeit, DNAzyme auf unterschiedliche Art zu modifizieren, ergeben sich zusätzlich interessante Möglichkeiten zur Optimierung dieser Antisense-Technologie. In dieser Arbeit wurde das GATA-3-spezifische DNAzym hgd40 mit den Modifizierungen eines inversen Thymidins am 3´-Ende, Phosphothioatverbindungen, 2´-O-Methylgruppen und Locked nucleic acids versehen. Das DNAzym und die entwickelten Varianten wurden funktionell charakterisiert, insbesondere wurde der Einfluss der vorgenommenen Modifikationen auf die Zugänglichkeit gegenüber der Zielsequenz sowie auf die katalytische Effizienz untersucht. Weiterhin wurden die Aktivität in Abhängigkeit des Magnesiummilieus analysiert und die GATA-3-DNAzyme in einem in vitro System hinsichtlich einer Auslösung möglicher Nebenwirkungen überprüft. Analysen zur Spaltungsaktivität ergaben, dass alle entwickelten Varianten außer das mit 2’-O-Methylgruppen versehene hgd40-OMe3 sowie das mit LNA versehene hgd40-L2 die GATA-3-cRNA spalten konnten. Die mit inversem Thymidin am 3´-Ende modifizierte Variante hgd40-3M und die mit LNA versehene Variante hgd40-L3 wiesen eine ähnlich hohe bzw. leicht verbesserte Spaltungseffizienz im Vergleich mit dem unmodifizierten hgd40-DNAzym auf. Hinsichtlich des Magnesiummilieus zeigte sich für alle verwendeten DNAzyme eine hohe Aktivität auch bei physiologischen Magnesiumkonzentrationen, welches auf eine hohe Aktivität in vivo hoffen lässt. Im Hinblick auf mögliche Off-Target-Effekte konnte in Zellkultur-Experimenten ausgeschlossen werden, dass die DNAzym-Varianten eine Aktivierung angeborener Immunmechanismen, insbesondere durch Interaktion mit dem Toll-like-Rezeptor 9, bewirken. Abschließend kann festgestellt werden, dass ein zukünftiger Einsatz eines modifizierten GATA-3-spezifischen hgd40-DNAzyms als neue Therapiestrategie bei Asthma bronchiale vielversprechend erscheint. Dies sollte in weiterführenden Untersuchungen in vivo überprüft werden.

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