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A. M. Siddiqui, M. J. Richards, S. J. Fliesler; Global Differential and Temporal Transcriptional Profiling of Retinas From AY9944-Treated (SLOS) vs. Control Rats. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2498.
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Treatment of Sprague Dawley rats with AY9944, an inhibitor of dehydrocholesterol-Δ7-reductase, produces an animal model of Smith-Lemli-Opitz Syndrome (SLOS), including grossly elevated 7-dehydrocholesterol and diminished cholesterol levels in all tissues and progressive retinal degeneration (Fliesler et al., Arch. Ophthalmol. 122:1190, 2004). We analyzed the differential gene expression profiles in retinas from this SLOS rat model compared to age-matched controls.
Sprague Dawley rats were treated with AY9944 as previously described (Fliesler et al., 2004) for 1, 2, and 3 mo; control litters (age- and sex-matched) received no drug. All animals were maintained under dim cyclic light (12L:12D, 20-40 lux) and fed a cholesterol-free diet and water ad lib. Total RNA was extracted from individual retinas, and mRNA was amplified and labeled (Affymetrix). Global gene-expression analysis was conducted using Affymetrix GeneChip Rat Genome 230 2.0 high-density arrays (probing 28,000 well-characterized rat genes). Retinas from AY9944-treated rats were compared to age-matched controls (N=3 per condition and age); a two-way ANOVA was performed and gene expression variability evaluated with regard to AY9944 treatment, age, and random noise (P-value ≤ 0.01). Functional category over-representation for each significant gene list was statistically analyzed using EASE/DAVID software (http://david.abcc.ncifcrf.gov).
ANOVA-derived interaction effects between age and AY9944 treatment yielded 27, 1223, and 544 significant differentially expressed genes at 1, 2, and 3 mo, respectively. EASE/DAVID analysis revealed that genes involved in multiple biochemical pathways are affected, including (among others) fatty acid metabolism, oxidative stress response, cell death/survival, visual transduction, and complement component activation. Notably, sterol metabolism genes were consistently down-regulated at all ages (AY9944 vs. control).
Retinal degeneration in the SLOS rat model involves differential, age-dependent alterations in multiple genes, with global metabolic involvement not restricted to the sterol pathway. In particular, dramatic gene expression changes occur at 2 mo, a transition point between near-normalcy (1 mo) and obvious histological degeneration and physiological dysfunction (3 mo).
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