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E. C. Johnson, L. Jia, W. O. Cepurna, S. K. McWeeney, S. Mongoue-Tchokote, J. C. Morrison; Altered Gene Expression Due to Initial Optic Nerve Head Injury in a Rat Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3278.
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© ARVO (1962-2015); The Authors (2016-present)
The anterior optic nerve head (ONH) is the principal site of initial injury in glaucoma and elevated intraocular pressure (IOP) is the predominant risk factor for the disease. Using a rat glaucoma model and microarray analysis, we previously identified gene expression changes in 1 mm ONH segments from eyes with long term pressure exposure and extensive optic nerve injury. This study is limited to the initial 0.4 mm unmyelinated ONH and designed to isolate expression changes associated with initial, focal injury.
ONH RNA was obtained following unilateral hypertonic saline injection to elevate IOP. Following optic nerve injury grading, four ONH groups were formed: (1) untreated fellows, (2) short term, higher IOP with focal optic nerve injury, (3) long term, lower IOP with focal nerve injury, and (4) long term, extensive nerve injury. Gene expression in each sample was determined using cDNA microarrays (N=28 arrays). Data were lowess normalized, thresholded and outliers flagged. ANOVA, with post-tests, was used to identify transcripts similarly altered in expression in both of the two focal injury groups (>1.3 fold change, p<0.05). Genes maximally altered by focal injury were isolated by excluding those with significantly greater change in the extensive injury group. DAVID website tools were used to identify significantly affected gene categories.
Analysis identified 1233 significantly and similarly regulated genes (689 up- and 544 downregulated) shared by the two focal injury groups. Genes upregulated >3 fold were Pttg1, Tnc, Ttk, Igfbp3, Spbc25, Socs3, Fbln2, Lmnb1, Kcns3, Tnfrsf12a, Mmp7 and Galnt3, while downregulated to <-3 fold were Aldh1a1, Id2, Aldoc, Unc13c, Sox21, Adamtsl1, Fmn2 and Ctnnd. Upregulated gene categories included cell proliferation, cell adhesion, cytoskeleton, lysosome, extracellular matrix, and immune response, while downregulated were adhesion and RNA polymerase II transcription factor activity (p<0.05).
This study identifies ONH genes and gene categories that are differentially and maximally regulated coincident with focal optic nerve injury resulting from elevated IOP. Since these changes appear associated with the initial injury to the ONH, rather than to extreme IOP levels or the onset of gliotic scarring, a further investigation of their specific roles in ONH injury is likely to suggest new targets for therapeutic intervention designed to prevent further axonal injury in glaucoma.
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