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E.C. Johnson, L. Jia, W.O. Cepurna, S.L. Barber, J.C. Morrison; Altered Optic Nerve Head Gene Expression in Response to Elevated Intraocular Pressure the Rat, a Microarray Analysis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1243.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: This study employs the powerful technique of microarray analysis to perform the first genome wide–analysis of altered gene expression in the optic nerve head (ONH) following exposure to experimentally elevated IOP. Methods: RNA (50 ng) was obtained from ONH (1 mm length) from injected and control, untreated rat eyes at 5 weeks following unilateral hypertonic saline injection to elevate IOP (N=6 per group). Injected eyes were matched for extensive and ongoing axonal degeneration in the retrobulbar optic nerve. Following 2 cycles of linear amplification, gene expression in each sample was independently determined using a reference standard study design and spotted cDNA microarrays (over 15,000 genes representing about half the genome). Data from each of the 12 arrays were normalized (Robust Linear Regression) and the two experimental groups compared using Significance Analysis of Microarrays to identify significant changes in gene expression (q<0.02, greater than 1.3 fold change, median False Discovery Rate of 2%). SOURCE, GenMapp and DAVID gene ontology websites were used to identify affected biological processes. Results: Of 1892 significantly altered genes identified in the Unigene database, 1269 were up– and 623 downregulated by elevated IOP. Upregulated processes, in terms of number of affected genes, were: cell cycle progression (41 genes), transcription regulation (57), ribosome biogenesis (37), protein biosynthesis (91), cell adhesion (37) and proteolysis (31). Downregulated processes included transcription regulation (37), metabolism (23) and transport (18). Those altered in expression by more than 2 fold included 177 up– and 43 downregulated genes. The most upregulated genes were periostin (12.8 fold) and tenascin C (6.1 fold), two extracellular matrix proteins associated with cell migration and adhesion. The most downregulated genes included four associated with steroid biosynthesis and transthyretin, a transport protein. Conclusions: In addition to documenting changes in gene expression associated with altered cell adhesion and increased proteolytic activity in the ONH injured by elevated IOP, this study demonstrates dramatic increases in tissue expression of genes associated with the cell proliferation and protein synthesis that mediate ONH remodeling. Further, it illustrates the potential use of this animal model to isolate the gene expression changes in the associated with initial ONH axonal injury due to elevated IOP. The identification of these genes is likely to suggest new targets for therapeutic intervention in glaucoma.
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