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Izzy Livne-Bar, Xiaoxin Guo, Jeremy M. Sivak; Establishing a New Mouse Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2484.
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Normal tension glaucoma (NTG) makes up a substantial group of glaucoma patients who experience vision loss in the absence of sustained increases in intraocular pressure. Research into early events in NTG is hindered by lack of genetically accessible models. We set out to develop a mouse NTG model that would facilitate research on the pathogenic mechanisms of this glaucoma subtype. In previous rat studies, chronic delivery of the vasoconstrictor peptide endothelin-1 (ET-1) into the optic nerve caused reduced blood flow and retinal ganglion cell (RGC) loss. Based on these reports, we aim to induce RGC and glial insult as well as ischemic stress by chronically over- expressing ET-1 in the mouse retina.
Adult C57BL/6 mice received intravitreal injection of Adenovirus vector encoding human ET-1 together with a ,GFP expressing, Adenovirus vector. Control mice received the GFP vector alone. Injected eyes were harvested six weeks later and processed for immunofluorescent analysis to determine retinal damage or loss of RGCs. In addition we evaluated markers of ischemic stress and inflammation.
Analysis at six weeks post injection showed a reduction of 37 % in the number of RGCs in ET-1 expressing eyes, compared to eyes expressing the GFP control. Increased expression of glial fibrilary acidic protein (GFAP) is an indicator of glial activation. Our preliminary data show increased levels of GFAP protein in retinal Muller cells, suggesting that ET-1 over expression stimulated glial activation. We are further characterizing this ET-1 induced phenotype in the wild type C57BL/6 strain and in an intraocular-pressure induced mouse glaucoma model (DBA/2J).
Our data indicate that ET-1 over expression in the mouse retina is likely to prove an important genetic model for the study of retinal ischemia and NTG. This form of the disease accounts, in some populations, to a majority of primary open-angle glaucoma patients and is in dire need of relevant research models.
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