Dokument: Charakterisierung der Sirt1 Expression im Mausgehirn - speziell in den Oligodendrozyten -
| Titel: | Charakterisierung der Sirt1 Expression im Mausgehirn - speziell in den Oligodendrozyten - | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=30889 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20141002-075444-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Eckstein, Denise [Autor] | |||||||
| Dateien: |
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| Beitragende: | Professor Aktas, Orhan [Gutachter] Prof. Dr. Schulz, Wolfgang A. [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Sirt1 ist eine biologisch hoch konservierte Histon-Deazetylase (HDAC) der Gruppe III, die über einen Nikotinamid-Adenin-Dinukleotid (NAD+) abhängigen Mechanismus die Lysinreste in Proteinen deazetyliert und zahlreiche relevante zellbiologische Funktionen ausübt. In den Stammzellnischen des adulten Gehirns existieren selbst erneuernde neurale Vorläuferzellen (NVZ), die Neurone, Astrozyten und Oligodendrozyten generieren können. Es ist bekannt, dass Sirt1 in die Differenzierung von NVZ involviert ist, unter oxidativen Bedingungen die Differenzierung in Richtung der Astrozyten lenkt und unter den entzündlich demyelinisieren-den Bedingungen der EAE (experimentelle autoimmune Enzephalomyelitis als Tiermodell der Multiplen Sklerose) vermehrt exprimiert wird (5). Die mangelnde Remyelinisierung in diesen Erkrankungen ist unter anderem auf unzureichende Regenerationsfähigkeit der Oligodendrozyten zurückzuführen. Einerseits ist bekannt, dass HDAC der Gruppen I und II für die gezielte Differenzierung von Oligodendrozyten notwendig sind (99). Andererseits wurde in Oligodendrozytenvorläuferzellen (OVZ) mit ausgeschalteter Sirt2 Funktion (HDAC Gruppe III) in vitro eine Differenzierung der Zellen in ein reiferes Stadium beobachtet (81). Der Einfluss von Sirt1 auf die Zelllinie der Oligodendrozyten hingegen ist weitgehend unbekannt. Daher stellte sich für die vorliegende Arbeit die Frage, ob auch Sirt1 sich in den Zellen der Oligodendrozytenlinie findet, dort einen Einfluss auf die Differenzierung hat und ob die Expression von Sirt1 dort sich in der EAE verändert.
In der vorliegenden Arbeit erfolgte zunächst eine Charakterisierung der physiologischen Expressionsmuster von Sirt1 im gesunden Mausgehirn mittels Immunfluoreszenz (IF) und qRT-PCR, gefolgt von in vitro Experimenten zur spontanen Differenzierungsfähigkeit von Sirt1Δex4/Δex4 NVZ (konditioneller Knockout des katalytischen Zentrums (129Sv.129Sv (C57BL/6)-SIRT1tm)) und einer Analyse der Sirt1Δex4/Δex4 Mausembryonen im Vergleich zu Wildtyp-Geschwistern. Die Sirt1 Expression in der EAE in C57/B6 Mäusen wurde via qRT-PCR, IF und Western Blot analysiert. Es stellte sich heraus, dass Sirt1 in den Keimzellregionen (SVZ und SGZ) des adulten Mausgehirnes in multipotenten Stammzellen (Nestin/Sox2), aber auch in den spezifischen OVZ (PDGFR) exprimiert wird. Weiterhin fand sich Sirt1 im Kleinhirnmark adulter Mausgehirne in differenzierten Oligodendrozyten, aber vor allem in den OVZ. Bei Abwesenheit funktionalen Sirt1 Proteins in Sirt1Δex4/Δex4 NVZ-Kulturen in vitro war im qRT-PCR Screening eine Reduktion von Zellzyklusinhibitoren (wie zum Beispiel p21 und PTEN) und Inhibitoren der OVZ Differenzierung (wie zum Beispiel Hes5 und insbesondere ID2) nachweisbar. Im Einklang damit waren die Marker der OVZ Differenzierung (Mash1, Sox10) erhöht. In der Immunhistochemie der Sirt1Δex4/Δex4 NVZ-Kulturen konnte dieser Effekt der Induktion der Oligodendrozytendifferenzierung bei Verlust des funktionalen Sirt1 Proteins ebenfalls gezeigt werden. Dies wird durch unsere Beobachtung unterstützt, dass Sirt1Δex4/Δex4 Mäuse (E17) in der Mehrzahl eine deutlich verfrühte Expression der Myelinmarker (MBP, CNPase) zeigten. Die Stammzelllokalisation und –anzahl (Sox2) war in diesen Tieren nicht verändert. Sirt1 wurde unter den inflammatorischen Bedingungen der EAE im Kleinhirn induziert. Sirt1 fand sich aber nicht in der ortsständigen Mikroglia (Iba1) und nur vereinzelt in einwandernden Monozyten (Ly6c). Sirt1 war in den OVZ (PDGFα, NG2) im Kleinhirnmark unter den Bedingungen der EAE signifikant vermehrt exprimiert. Zusammenfassend ergaben sich Hinweise, dass Sirt1 die Differenzierung zu reifen Oligodendrozyten inhibiert. Dies konnte unlängst durch eine unabhängige Publikation bestätigt werden (6). Es könnte durch selektive Sirt1 Inaktivierung ein neuer Ansatz in der regenerativen Therapie demyelinisierender Erkrankungen gefunden werden. | |||||||
| Quelle: | Literaturverzeichnis
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| Rechtliche Vermerke: | Hiermit erklärt der Autor folgendes bezüglich vier Abbildungen aus der Einleitung, die lediglich den Inhalt der Einleitung verdeutlichen und keinen Anteil an der wissenschaftlichen Leistung der Dissertation haben:
1. Abbildung 2 ist gemäß Zitat in der Arbeit aus Stromnes 2006 (2) entnommen. Hierzu liegt eine Genehmigung der „Nature Publishing Group“ vor diese Abbildung in gedruckter und elektronischer Form im Rahmen meiner Dissertation gemäß den Bedingungen des Vertrages (License Number 3464360496909) zu nutzen. 2. Abbildung 3 ist gemäß dem Zitat in der Arbeit aus Yang 2006 (1) entnommen. Hierzu liegt eine Genehmigung von „Springer“ vor diese Abbildung im Rahmen meiner Dissertation gemäß den Bedingungen des Vertrages (License Number 3464370860554) zu nutzen. Dies beinhaltet ebenfalls eine elektronische Version im Magazin/Speicher der Universität inklusive UMI. 3. Abbildung 4 ist in den öffentlichen Besitz übergeben worden. Das heißt sie darf von jedem ohne jede Bedingungen für jeden Zweck genutzt werden, solange keine geltenden Gesetze gebrochen werden. 4. Abbildung 6 beinhaltet Teile, die im Rahmen eines „open access“ 2008 von Arias-Carrion (4) veröffentlicht worden sind und gemäß der angegebenen Lizenz ohne Einschränkungen verändert und veröffentlicht werden dürfen. Bezüglich dieser oben genannten Abbildungen ist der Autor dann natürlich NICHT „allein berechtigt, über die urheberrechtlichen Nutzungsrechte zu verfügen“, sondern darf sie lediglich im Rahmen der Dissertation in oben aufgeführter Weise nutzen. Der Rest der Arbeit bleibt davon unberührt, hier liegt das Urheberrecht beim Autor. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 02.10.2014 | |||||||
| Dateien geändert am: | 02.10.2014 | |||||||
| Promotionsantrag am: | 16.12.2013 | |||||||
| Datum der Promotion: | 12.08.2014 |
