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S. Kitambi, R. T. Peterson, J. Malicki; The Use of Small Molecule Screens in the Zebrafish Model to Analyze Normal and Pathological Processes in the Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5778.
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The zebrafish larva is becoming increasingly popular as a tool for the identification of small molecules that affect developmental and physiological processes. The strength of this model is the efficiency of subjecting zebrafish larvae to a large variety of chemical compounds in a short time. The purpose of this study is to test the zebrafish larva as a tool for the identification of compounds that affect both normal and pathological processes relevant to human eye diseases.
Zebrafish embryos were subjected to in excess of 2000 compounds from small molecule libraries and tested for changes in two processes relevant to human retinal pathologies: (1) the differentiation of blood vessels, and (2) the survival of photoreceptor cells. The first of these tests was performed on wild-type animals, the second on several mutant strains that carry genetic defects of photoreceptor survival. In both cases, GFP transgenes were used to visualize relevant structures: fli1:EGFP transgene to highlight blood vessels and rod opsin:GFP construct to visualize photoreceptor cells. The latter transgene was crossed into several zebrafish mutant lines that display photoreceptor defects, including ovl, mok, ako, and eli.
The screening for compounds affecting the differentiation of blood vessels resulted in the identification of five small molecules which affect retinal vasculature. Two of the five compounds result in thickened and fused hyaloid vessels; one compound produces thick hyaloid vessels, one fused but not obviously thickened vessels, and finally one compound produces reduction or absence of hyaloid vessels. These defects appear to be specific to the retina as the trunk vasculature appears to be grossly normal. The mode of action of these compounds is being explored. In parallel, zebrafish mutant lines displaying photoreceptor degeneration that carry opsin:GFP transgene are being used to screen for small molecules that slow down photoreceptor loss.
The zebrafish is an effective animal model to search for small molecules that affect normal as well as pathological processes in the retina. The identified chemical compounds have potential therapeutic importance.
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