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M. A. Chrenek, A. C. Ziesel, J. Wisard, R. Darrow, L. Barsalou, D. T. Organisciak, P. Wong, J. M. Nickerson; Retinal Gene Expression Changes in Animal Models of Light Induced- and Genetic- Retinal Degenerations. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3404.
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We hypothesized that molecular mechanisms in the retina that respond to stress and apoptosis would be similar between disparate model systems. In this case we compare the well studied light induced retinal damage (LIRD) model in rats to the degeneration in IRBP knockout (-/-) mice.
Dark-reared Sprague Dawley rats were treated with 1200 lux of green light, beginning at 9AM, for 16 hours. Light treated and unexposed control rats were sacrificed at the same time. Cyclic reared IRBP-/- mice were sacrificed at P20 and P25, before and during retinal degeneration. Total retinal RNA was prepared from 7 rats and 15 mice per time point. Changes in mRNA abundance were quantified with Illumina microarrays (Emory Biomarker Service Center), and analyses were done using R and BioConductor software. TUNEL and outer nuclear layer (ONL) thickness measurements were done to assess the extent of retinal degeneration.
Apoptosis was induced in photoreceptor cells of Sprague Dawley rats exposed to 16 hours of light and confirmed by TUNEL. In the IRBP-/- mouse model TUNEL positive photoreceptor cell apoptosis was apparent at P25. By P25, the ONL in the IRBP-/- mice had also thinned to ~70% of the ONL at P20. Microarray results for the two models showed similar changes in retinal gene expression. Genes involved in vision (such as rhodopsin and phosphodiesterase) were down regulated, while those involved in the stress response (heme oxygenase, heat shock proteins) and apoptosis (caspases 3 and 7) were up regulated.
The down regulation of visual function genes appears to occur both as a response to intense light and in response to a decrease in the relative number of photoreceptor cells in the retina. The up regulation of genes involved in stress response and apoptosis in LIRD are due primarily to oxidative stress. The similar gene expression profile in the IRBP-/- mouse model of retinal degeneration suggests that oxidative stress also occurs in this model.
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