T- Zell-Erschöpfung
5.6.14 Microarray
Die Microarray Rohdaten wurden durch die Zentrale Forschungseinrichtung Transcriptomics der Medizinischen Hochschule Hannover (Research Core Unit Transcriptomics (RCUT) of Hannover Medical School) generiert.
Bei der Prozessierung der RNA-Proben wurden diese zu cRNA revers transkribiert, amplifiziert und mit Fluorophoren (Cy3, Emission bei 570 nm) markiert und die cRNA fragmentiert. Die Synthese der Cy3-markierten cRNA wurde mit dem Quick Amp Labeling kit (Fa. Agilent, 5190-0442) entsprechend den Herstellerangaben durchgeführt. Die Fragmentierung der cRNA, die Hybridisierung und anschließenden Waschschritte wurden nach den Empfehlungen des Herstellers (One-Color Microarray-Based Gene Expression Analysis Protocol V5.7 (Fa. Agilent)) ausgeführt. Das Fragmentlängenprofil der amplifizierten cRNA-Proben wurde mit 2100 Bioanalyzer analysiert. Der Microarray Hybridisierungsofen (Fa. Agilent) wurde benutzt, um über Nacht die cRNA auf die Microarray Objektträger zu hybridisieren. Die Gesamtmenge der für die Hybridisierung benutzten cRNA betrug 130 ng.
Es wurde der „026655AsQuadruplicatesOn4x180k Mus musculus Microarray“ durchgeführt (Microarray ID (AMADID): 048306). Hierbei handelte es sich um eine verfeinerte Version des Gesamt Maus-Genom Oligo Microarrays (Whole Mouse Genome Oligo Microarray 4x44K v2 (AMADID 026655, Fa. Agilent Technologies)), die in der Zentralen Forschungseinrichtung Transcriptomics der Medizinischen Hochschule Hannover entwickelt wurde. Das Muster des Microarrays wurde im Agilent’s eArray-Portal definiert und verwendete ein 4x180k Musterformat für mRNA-Expression als Matrize. Auf ein 180k Microarray wurden alle nicht-Kontroll-Sonden von AMADID 026655 vier Mal aufgetragen (auf dem Chip ausgeführte Quadruplikate). Dies ermöglichte die 4-fache Messung einer Sonde, wodurch die quantitative Verlässlichkeit im niedrigeren Intensitätsbereich bei der späteren Messung der Fluoreszenzintensität steigt und auch mit initial eingesetzten geringen RNA-Mengen (5 - 50 ng) eine Microarray Analyse möglich war. Die Kontroll-Sonden, die für die Extraktion der Daten mit geeigneten Programm-Algorithmen benötigt wurden, wurden mit eArray bestimmt und automatisch platziert. Die Objektträger wurden mit dem Microarray Scanner G2565CA (Fa. Agilent) (Pixelauflösung 5 µm, Bittiefe 20) gescannt. Die Daten wurden
mittels Feature Extraction Software V10.7.3.1 unter Verwendung der Protokoll-Datei GE1_107_Sep09.xml durchgeführt. Die prozessierten Intensitätswerte (gProcessedSignal oder gPS) wurden entsprechend des Array-spezifischen Skalierungsfaktors normalisiert.
Bei den dargestellten Werten aus dem Microarray handelt es sich um die normalisierten Daten der Fluoreszenzintensität der einzelnen erkannten mRNA-Transkripte, die aus den individuellen Proben stammten.
Statistische Auswertung 5.7
Die Bestimmung der statistischen Signifikanz wurde mittels Zweistichproben-t-Test (unpaired t test) für zwei unabhängige Stichproben, durch den Rangkorrelationskoeffizienten nach Spearman (rs) und Log-rank (Mantel-Cox) Test ermittelt, wobei das Programm GraphPad Prism®, Version 5.04 (Fa.
GraphPad Software) benutzt wurde. Für die statistische Auswertung wurde die Standardabweichung (standard deviation) benutzt (± SD). Für die Darstellung der statistischen Signifikanz wurde folgendes Schema verwendet:
ns nicht signifikant P > 0.05
* signifikant P ≤ 0.05
** sehr signifikant P ≤ 0.01
*** hoch signifikant P ≤ 0.001
**** höchst signifikant P ≤ 0.0001
Für die Interpretation des Korrlationskoeffizienten (rs) galt:
rs = -1 inverse Korrelation (K);
rs = -0,9 > -0,1 variable (K);
rs = 0,0 keine (K);
rs = 0,1 < 0,9 variable (K);
rs = 1 perfekte Korrelation (K)
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