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Diana C Lozano, Dongseok Choi, Hari Jayaram, William O Cepurna, Tiffany E Choe, Lauren Davis, Shandiz Tehrani, Elaine C. Johnson, John C Morrison; Persistent Changes in Optic Nerve Head (ONH) Gene Expression Following an Elevated Intraocular Pressure Event. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2544.
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© ARVO (1962-2015); The Authors (2016-present)
To determine if an 8 hour period of controlled elevation of intraocular pressure (CEI) produces persistent gene expression changes in the rat ONH.
Anesthetized rats were exposed unilaterally to an 8-hour CEI at 60 mm Hg and physiological parameters monitored throughout the experiment. Optic nerves were collected and graded for injury on a scale from 1 (normal) to 5 (>50% of axons degenerating). ONH RNA was extracted, libraries prepared and gene expression compared between naïve (n = 8) and 10-day post-CEI ONH (n=6) using RNA-seq. Sequenced data were mapped to the UC Santa Cruz genome (version rn 6) and unique reads were normalized by the trimmed mean of M-values method. A generalized linear model method with likelihood ratio tests was used to identify differentially expressed genes. All statistical computations were made using the Bioconductor packages in R-statistical language. Genes with false discovery adjusted p-value <0.05 were considered statistically significant. DAVID Bioinformatics tools were used to identify significant gene clusters (enrichment score > 1.3).
Mean CEI optic nerve injury grade was 1.95 ± 0.42 (approximately 12% of axons degenerating), compared to 1.01 ± 0.01 in naïve nerves. In CEI ONH, there were 235 significantly regulated genes (104 up and 131 down) compared to naïve. Significantly upregulated clusters included extracellular, immune, responses to stimuli, cell proliferation, angiogenesis, and various regulatory processes. Axonal cytoskeletal and synaptic cell compartments and signaling dominated in down regulated gene clusters, which also included lipid biosynthesis. Although only a small portion of axons appeared to be degenerating, axonal messages at 10 days were decreased by an average of 45%.
Significantly altered ONH gene expression responses persist at 10 days following a single exposure to a period of IOP elevation that is survived by most optic nerve axons. This suggests the presence of long-term changes in the microenvironment of the ONH. Such changes may increase or decrease axonal sensitivity to subsequent IOP insults, and shed light on the role of fluctuating IOP in glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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