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Kazuya Oikawa, James N Ver Hoeve, Leandro B C Teixeira, Julie Kiland, Elizabeth Hennes-Beean, Carol A Rasmussen, Xiao-yu Liu, Akihiro Ikeda, Matthew Ellinwood, Gillian J McLellan; Early changes in optic nerve head (ONH) gene expression in a spontaneous glaucoma model. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
The early pathophysiology of glaucomatous optic neuropathy remains poorly understood although evidence points to the lamina cribrosa region of the ONH as an initial site of damage. The purpose of this study was to characterize early changes in structure, function and transcriptome of ONH in a spontaneous large animal glaucoma model.
Nineteen 10-12 week-old cats (11 homozygous for recessively inherited feline congenital glaucoma [FCG]; 8 normal) were studied. IOP was measured 3x/wk by rebound tonometry. ONH cube and raster scans were acquired by SD-OCT. Root mean square (RMS) of the early wavelets and peak amplitudes of the late positive component (P2) were calculated for VEP responses. Following euthanasia, RNA was extracted from ONHs for RNA sequencing (RNA-seq; Illumina Hiseq 2000).Raw reads were filtered and aligned to the Felis catus reference genome. Transcript abundances were estimated and differentially expressed genes (DEGs) identified by R/Bioconductor package. Weighted gene co-expression network analysis (WGCNA) was applied based on unsupervised hierarchical clustering approach. Optic nerve axons were quantified using a semi-automated targeted sampling method. Data from one eye per cat were compared between groups by two-tailed unpaired t-tests, with p<0.05 considered significant.
In FCG cats, mean [SD] IOP (18.7 [5.0] mmHg) was significantly higher (12.8 [0.8] mmHg; p=0.0014), and VEP P2 amplitude and RMS were significantly lower than normal (p=0.045, and 0.024, respectively). Compared to normal cats, the ONH in FCG had significantly increased optic cup depth and reduced pre-laminar tissue thickness (p=0.028 and 0.007, respectively). However, mean axon counts were not significantly different. RNA-seq analysis detected over 200 DEGs with FDR<0.05, where the functions of cell proliferation, immune and inflammatory responses were overrepresented. WGCNA identified gene clusters that strongly correlated with disease status (r2=0.65, p<0.01). These clusters contained Toll-like receptor and Fc receptor signaling pathway related genes that were over-expressed in glaucoma.
Early life IOP elevation, ONH remodeling, and optic nerve functional impairment precede irreversible axon loss in this unique large animal model. Our findings support cell activation, proliferation and immune responses in the ONH as early molecular events in the pathobiology of spontaneous glaucoma.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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