Purchase this article with an account.
K.S. Kompass, O.A. Agapova, P.L. Kaufman, C. Rasmussen, B.T. Gabelt, M.R. Hernandez; Transcriptional Changes in the Optic Nerve Head (ONH) in a Primate Model of Ocular Hypertension (OHT) Determined by Oligonucleotide Microarrays . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1253.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: While anatomical changes occurring in POAG are well–characterized, transcriptional changes preceding them in OHT–mild glaucoma are not, nor is there an established model of transcriptional events characteristic of each stage of degeneration. We are using an in vivo model to quantify early transcriptional events that precede clinically detectable optic nerve degeneration, and to quantify transcriptional events that are active during intermediate and advanced stages of degeneration. Methods: We used a laser model of scarification of the trabecular meshwork in order to experimentally elevate IOP in one eye in four cynomolgous monkeys (Macaca fascicularis) for 16–38 weeks. Myelinated optic nerves were processed post–mortem to determine the degree of neuronal loss. Contralateral eyes were used as controls. Total RNA isolation, amplification, hybridization to Affymetrix oligo. arrays (three replicates per eye), and scanning of hybridized arrays was performed. For each gene, fold change was calculated for each monkey between the experimental and control eye. We used RMA (Irizarry et al., 2003) and Li–Wong (Li and Wong, 2001) normalization methods, and t–test and empirical Bayes statistics (Smyth, 2004) to find highly significant genes (P<0.005) differentially expressed between control and experimental eyes. Results: In OHT–mild experimental glaucoma, genes coding for antioxidant enzymes, signal transduction messengers, mitochondrial carriers and cytoskeletal proteins were upregulated. mRNA for neurofilaments was upregulated at least 2fold in the mild ExpG–OHT. Gap junction protein beta 1 (GJB1), stathmin–like 4 (STMN4), aquaporin 4 (AQP4) and myelin associated glycoprotein (MAG) were upregulated at least 1.5fold in OHT–mild but returned to control levels with increased axonal loss. In advanced ExpG, genes encoding tissue remodeling and neural degeneration were upregulated. Extracellular proteases such as cathepsins and other proteases including lysozyme (LYZ) were upregulated at least 2fold. Apolipoprotein E (APOE) was upregulated in all monkeys and upregulation increased with axonal loss. Conclusions: Initial data has shown that unique and overlapping transcriptional changes occur at distinct stages of optic nerve degeneration. This data may provide a framework to understand genomic regulatory changes in the transition from mild ExpG–OHT to advanced ExpG.
This PDF is available to Subscribers Only