Dokument: Die Rolle des Transkriptionsfaktor HIF-1 bei der strahlungsbedingten Hautschädigung und Signaltransduktion in Hautzellen
| Titel: | Die Rolle des Transkriptionsfaktor HIF-1 bei der strahlungsbedingten Hautschädigung und Signaltransduktion in Hautzellen | |||||||
| Weiterer Titel: | The role of the transcription factor HIF-1 in radiation-induced skin damage and signal transduction in skin cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=34738 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20150709-110649-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | M. Sc. Sondenheimer, Kevin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Krutmann, Jean [Betreuer/Doktorvater] Prof. Dr. Urlacher, Vlada [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Ultraviolette (UV) Strahlung, insbesondere der energiereichste Teil des solaren Spektrums, die UVB-Strahlung, gehört zu den wichtigsten Umweltfaktoren, die eine Schädigung der Haut, wie z.B. die Entwicklung von Hautkrebs und vorzeitiger Hautalterung, hervorrufen. Dies ist wesentlich bedingt durch die Fähigkeit von UVB-Strahlung direkte DNS-Schäden zu verursachen. Zellen haben zum Schutz vor exogenen und endogenen Noxen hochspezialisierte Kompensationsmechanismen entwickelt. Hierzu zählt die DNS-Reparatur. Eine funktionierende DNS-Reparatur ist essentiell für das Überleben der Zelle und die Vermeidung von Mutationen. Der Hypoxie-Induzierbare Faktor (HIF)-1α ist ein wichtiger Regulator bei der zellulären Stressantwort und spielt besonders bei der Adaptation an Hypoxie eine große Rolle. Vor kurzem konnte gezeigt werden, dass dieser Transkriptionsfaktor auch in der Regulation der UVB-induzierten DNS-Reparatur von Bedeutung ist.
Das Ziel der vorliegenden Arbeit war es, die Funktion von HIF-1 in einem konditionalen Mausmodell, welches eine gezielte Deletion von HIF-1α in den Keratinozyten der Oberhaut ermöglicht, bei der UVB-induzierten Stressantwort zu untersuchen. Darüber hinaus sollten neue Mechanismen in der Photokarzinogenese und der UV-induzierten Hautalterung aufgedeckt werden, die eine Beteiligung von HIF-1α zeigen. In HIF-1α profizienten murinen Keratinozyten konnte in vitro eine UVB abhängige Stabilisierung von HIF-1α nachgewiesen werden, die eine erhöhte mRNS- und Protein Expression der DNS-Reparaturenzyme CSA, CSB, XPB und XPG zur Folge hatte. Im Gegensatz dazu waren diese Reparaturproteine in HIF-1α defizienten Zellen nicht verstärkt exprimiert und es zeigte sich eine deutlich verminderte UVB-induzierte CPD-Reparatur. In zwei in vivo Experimenten wurde ein bislang unbekannter HIF-1α spezifischer Einfluss auf die Pigmentierung und die Faltenbildung der Maushaut identifiziert. Eine die Keratinozyten betreffende Deletion von HIF-1α führte zu einer erhöhten UVB-induzierten Pigmentierung, aber zu einer geringeren Faltenbildung. Zudem wiesen HIF-1α defiziente Mäuse verstärkte UVB-induzierte Hautschäden auf. Es wurde eine verstärkte epidermale Hyperplasie, ein erhöhter transepidermaler Wasserverlust und eine verstärkte Reduktion des subkutanen Fettgewebes beobachtet. Die Entdeckung, dass der Transkriptionsfaktor HIF-1α ein wichtiger Regulator in der UVB-induzierten DNS-Reparatur ist, könnte zur Entwicklung neuer Behandlungsstrategien bei der Photokarzinogenese beitragen. Zusätzliche durch HIF-1α modulierte Signalwege bei der Melanogenese, der Faltenbildung und der strahlungsbedingten Hautschädigung lassen auf einen weitreichenden Einfluss dieses Transkriptionsfaktors in der Physiologie und Pathophysiologie der Haut schließen.Ultraviolet (UV) radiation, especially the part of the solar spectrum with the highest energy, the UVB radiation, is the major environmental factor responsible for skin damage for example skin carcinogenesis and premature skin aging. This is mainly induced by the ability of UVB-radiation to cause direct DNA damage. Cells have developed highly specialized compensatory mechanisms including DNA repair to cope with exogenous and endogenous noxae. A functional DNA repair is essential for the cell survival and to avoid mutations. The hypoxia-inducible factor (HIF)-1α is a major regulator of the cellular stress response and plays an important role especially in cellular adaptation to hypoxia. A few years ago, it was shown that this transcription factor is also involved in the regulation of the UVB-induced DNA repair. The aim of this work was to investigate the function of HIF-1 in the UVB-induced stress response by the use of a conditional mouse model which allows a specific deletion of HIF-1α in the keratinocytes of the epidermis. Moreover, new mechanisms of photocarcinogenesis and UV induced skin aging should be revealed, showing the involvement of HIF-1α. In HIF-1α proficient murine keratinocytes a UVB-dependent stabilization of HIF-1α was detected, which leads to an increased mRNA and protein expression of the DNA repair enzymes CSA, CSB, XPB and XPG. In contrast these repair proteins were not enhanced induced in HIF-1α deficient cells which leads to a significantly decreased CPD-repair. In two in vivo experiments a previously unknown influence of HIF-1α on the pigmentation and wrinkle formation of murine skin could be identified. A specific deletion of HIF-1α in keratinocytes led to an enhanced UVB-induced pigmentation but results in a reduced wrinkle formation. In addition HIF 1α deficient mice show several other UVB-induced changes of the skin including an enhanced epidermal hyperplasia, an increased loss of transepidermal water and an enhanced reduction of subcutaneous fat. The detection of the transcription factor HIF-1α as a regulator of the UVB-induced DNA repair can lead to development of new therapeutic strategies in photocarcinogenesis. Additional modulated HIF-1α pathways in the melanogenesis, the wrinkle formation and the radiation-induced skin damage lead to the suggestion that this transcription factor has a wide influence on physiology and pathophysiology of the skin. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | November 2011 - Mai 2015 | |||||||
| Fachbereich / Einrichtung: | Sonstige Einrichtungen/Externe » An-Institute » Institut für Umweltmedizinische Forschung (IUF) an der HHU | |||||||
| Dokument erstellt am: | 09.07.2015 | |||||||
| Dateien geändert am: | 09.07.2015 | |||||||
| Promotionsantrag am: | 07.05.0015 | |||||||
| Datum der Promotion: | 17.06.0015 |
