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Aus Dem Institut Für Pharmakologie Der Medizinischen Hochschule Hannover Aus dem Institut für Pharmakologie der Medizinischen Hochschule Hannover Aufbau einer Datenbank für die Archivierung, Visualisierung und Auswertung von mRNA-Expressionsprofilen entzündungsrelevanter Gene auf der Basis eines standardisierten Oligonukleotid-DNA-Mikroarray-Systems Dissertation zur Erlangung des Doktorgrades der Humanbiologie der Medizinischen Hochschule Hannover vorgelegt von Axel Hans Robert Weber aus Kusel Hannover 2006 Angenommen vom Senat der Medizinischen Hochschule Hannover am 12. Juli 2006 Gedruckt mit Genehmigung der Medizinischen Hochschule Hannover Präsident: Prof. Dr. Dieter Bitter-Suermann Referent: Prof. Dr. Helmut Holtmann Korreferenten: Prof. Dr. Herbert Matthies Prof. Dr. M. Lienhard Schmitz Tag der mündlichen Prüfung 19. Juli 2006 Danksagung Die Durchführung und Niederschrift dieser Arbeit wäre nicht möglich gewesen ohne die Unterstützung und Förderung zahlreicher Personen. Mein besonderer Dank gilt meinem Doktorvater Prof. Dr. Michael Kracht für die hervorragende fachliche Betreuung dieser Arbeit sowie für zahlreiche Anregungen und Diskussionen. Dank gebührt auch Prof. Dr. Klaus Resch für die vielfältige Unterstützung innerhalb des Institutes für Pharmakologie. Herrn Dr. Oliver Dittrich-Breiholz, danke ich für die fundierte Einführung in das Thema DNA-Mikroarrays, die vielen fruchtbaren Diskussionen und die gute Zusammenarbeit beim Aufbau der Datenbank. Heike Schneider danke ich für die stete Hilfsbereitschaft und die unermüdliche Dateneingabe. Auch möchte ich mich bei Prof. Edgar Wingender und Dr. Alexander Kel von BIOBASE bedanken für die Kooperation und Überlassung der Auswertungsergebnisse. Nicht zuletzt gilt mein Dank natürlich auch allen Kooperationspartnern des Z02- Projektes für die Bereitstellung der Daten, die die Grundlage dieser Arbeit bilden. Die Arbeit wurde im Rahmen des DFG-Sonderforschungsbereiches SFB 566 Zytokin- Rezeptoren und Zytokin-abhängige Signalwege als therapeutische Zielstrukturen, im Teilprojekt Z02, „Identifizierung von differenziell regulierten Genen mittels DNA Microarrays” erstellt. Dank gilt dem Präsidium der MHH, das die Stelle für dieses Projekt geschaffen hat. Inhaltsverzeichnis 1 Einleitung................................................................................................ 8 1.1 Mikroarray-Verfahren im Überblick...................................................................... 8 1.2 Vergleichbarkeit der Ergebnisse aus DNA-Mikroarray-Experimenten....................... 10 1.3 Informationsflüsse im Zusammenhang mit DNA-Mikroarray-Experimenten..............12 1.4 Prozessierung, Datenaufnahme und Ergebnisdarstellung von DNA-Mikroarray-Experimenten....................................................................... 12 1.5 Datenbanken für Mikroarray-Experimente und BASE............................................ 13 1.6 Möglichkeiten der Mikroarray-Technologie.......................................................... 15 1.7 Regulation der Genexpression während einer Entzündung als Paradigma für koordiniert ablaufende komplexe genregulatorische Vorgänge... 16 1.8 Algorithmen zur Vorhersage von Enhancer Elementen.......................................... 19 1.9 Fragestellung................................................................................................. 19 2 Material und Methoden ....................................................................... 20 2.1 CytoBASE und BASE....................................................................................... 20 2.2 Mikroarray-Experimente ................................................................................. 20 2.2.1 Mikroarray-Typen...................................................................................... 20 2.2.1.1 Allgemeiner Aufbau der Entzündungsarrays.............................................. 21 2.2.1.2 Entzündungsarrays............................................................................... 21 2.2.2 Die experimentelle Gruppe - parallele Prozessierung der Proben eines Experimentes................................... 23 2.2.2.1 Die experimentelle Gruppe und Arrayvergleiche........................................ 23 2.2.2.2 Rohdatensätze in CytoBASE sind Arrayvergleiche...................................... 24 2.2.2.3 Experimentelle Gruppen in CytoBASE...................................................... 25 2.2.3 Probenprozessierung.................................................................................. 25 2.2.3.1 cDNA-Synthese.................................................................................... 25 2.2.3.2 cRNA-Synthese und -Markierung............................................................ 25 2.2.3.3 Qualitätskontrolle der RNA und cDNA...................................................... 25 2.2.3.4 Hybridisierung..................................................................................... 26 2.2.4 Rohdatenerzeugung................................................................................... 26 2.2.4.1 Abtasten der Fluoreszenzintensitäten in Scan-Stufen................................. 26 2.2.4.2 Datenextraktion und -Quantifizierung mit Imagene................................... 26 2.2.5 Aufbereitung der Rohdaten......................................................................... 28 2.2.5.1 Integration von Daten mit MAVI Pro........................................................ 28 2.2.5.2 Normalisierung der Daten mit MAVI Pro................................................... 28 2.2.5.3 Qualitäts-Filterung und Zusammenfassung der Daten................................ 29 2.2.6 Rohdaten in CytoBASE............................................................................... 29 2.2.7 Integration aller Messwerte einer experimentellen Gruppe............................... 30 2.3 Server.......................................................................................................... 30 2.3.1 Hardware und Software.............................................................................. 30 2.3.2 Datenbankinstanzen.................................................................................. 31 2.4 Softwareentwicklung....................................................................................... 31 2.4.1 Programmiersprachen und Entwicklungsumgebung........................................ 31 2.4.2 Dokumentation......................................................................................... 31 3 Ergebnisse ........................................................................................... 32 3.1 Erweiterungen der Datenbank.......................................................................... 32 3.1.1 Erweiterungen von Tabellen aus BASE.......................................................... 32 3.1.1.1 Rohdaten und Gensonden...................................................................... 32 3.1.1.2 Dokumentation experimenteller Gruppen................................................. 33 3.1.1.3 Neue Benennung von „Analyzed data sets”...............................................34 3.1.2 Neue Tabellen in CytoBASE......................................................................... 34 3.1.2.1 Probenannotation und Suchfunktionen.....................................................34 3.2 Konzeptionelle Vorarbeiten für den Datenzugriff in CytoBASE.................................................................................................... 37 3.2.1 Nutzerkonzept und Gruppenzugehörigkeit..................................................... 37 3.2.2 Nomenklatur............................................................................................. 39 3.2.2.1 Die Probe – „Sample” und „Sample Description”....................................... 39 3.2.2.2 Der Rohdatensatz „Raw Data Set”........................................................... 41 3.2.2.3 Die Analysegruppe „Analysis Group”........................................................42 3.3 Datenimport nach CytoBASE............................................................................ 44 3.3.1 Rohdaten................................................................................................. 44 3.3.1.1 Das Werkzeug CytoBASE_Rohdatentool (mergerawfiles)............................ 44 3.3.1.2 Hochladen und Zusammenfassen der Rohdatensätze................................. 47 3.3.2 Annotation der RNA-Proben........................................................................ 48 3.4 CytoBASE – Erweiterungen gegenüber BASE.......................................................50 3.4.1 Benutzeroberfläche.................................................................................... 50 3.4.1.1 Startseite............................................................................................ 50 3.4.1.2 Benutzerhandbücher............................................................................. 51 3.4.1.3 Navigation und Datenanzeige................................................................. 52 3.4.1.4 Verweise für Gensonden zu GeneCards.................................................... 54 3.4.1.5 Neue Nomenklatur für CytoBASE-Elemente.............................................. 56 3.4.2 Eingabe und Verwaltung der Daten.............................................................. 56 3.4.2.1 Ausschluss doppelter Eintragungen......................................................... 56 3.4.2.2 Annotation der RNA-Proben................................................................... 57 3.4.2.3 Dokumentation der experimentellen Gruppe............................................
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