Comparative Analysis of Optic Nerve Head Gene Expression Changes in Human Glaucoma and in Rodent Models of Ocular Hypertension

Abstract

Abstract: : Purpose: To globally characterize abnormal gene expression patterns in the glaucomatous optic nerve head (ONH) and to evaluate whether surgical rodent models of ocular hypertension accurately reflect the molecular events in human glaucoma. Methods: Ocular hypertension (OHT) was induced in one eye of Brown Norway rats through diode laser cauterization of the trabecular meshwork. The second eye was left untreated and served as a control. The development of OHT was monitored by applanation tonometry and the pupil light reflex and electroretinogram were recorded to assess the degree of visual loss. Two and four weeks after surgery the optic nerve heads from both operated and control eyes were isolated. Following RNA extraction the gene expression patterns were determined using Affymetrix gene chips. Likewise, RNA was also extracted from the optic nerve heads of carefully selected human eye donors with glaucoma and from healthy controls. Gene expression profiles were established using gene Affymetrix chips. Data were analyzed to identify those genes whose expression patterns were conserved between our rat model and human glaucoma. Results: Statistical analyses of data obtained from ONH of rats with ocular hypertension identified approximately 60 genes which are more prominent in the degenerating optic nerve head. At least 75% of these also exhibited increased transcript levels in human glaucomatous ONH. Functionally, many of these genes can be classified as extracellular matrix constituents (e.g. COL10a1, TIMP1), regulators of cell division (e.g. GAS6), and adhesion molecules (e.g. CHAD). Conclusions: The gene expression changes observed in our rodent model of ocular hypertension largely reflected those evident in human glaucomatous tissue. Frequently, the magnitude of the observed expression change was less pronounced in human tissue than in the rodent model. The comparative analysis data derived from the animal models of glaucoma and human glaucomatous tissue can highlight common pathways, and also allows the identification of minor gene expression changes through focused data analysis.

Keywords: gene microarray • astrocytes: optic nerve head • candidate gene analysis