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Cornelia A Deeg, Patrizia Uhl, Barbara Amann, Andreas Blutke, Simone Renner, Sieglinde Hirmer, Juliane Merl-Pham, Walter Sekundo, Rüdiger Wanke, Eckhard Wolf, Stefanie M Hauck; The INSC94Y transgenic pig: a novel model for diabetic retinopathy with macular edema. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetes mellitus is associated with sight threatening pathophysiology at different sites of the eye. Diabetic retinopathy (DR) is a major cause of blindness, because of two vision threatening complications, proliferative retinopathy and macular edema. Therefore, we investigated the ocular phenotype of INSC94Y transgenic pigs, a novel model of Diabetes mellitus, for the presence of molecular pathologies replicating the human disease phenotype.
Eyes from 5 adult INSC94Y transgenic pigs and 5 matched controls were fixed and embedded for (immuno-) histochemistry for investigating histopathology. Retinal tissue was secured from the same animals and processed for proteomics. We used quantitative liquid chromatography-based mass spectrometry (LC-MSMS) with label-free quantification and pathway enrichment analyses for identification of disease-related molecular phenotypes.
Interestingly, in all INSC94Y transgenic pigs, besides cataract formation, there was significant macular edema detectable. Further, inflammation, microglia activation and a change in retinal vessels was evident. These changes are very similar to pathophysiology in DR patients; therefore this novel animal model is well suited to investigate molecular mechanisms. Differential proteome analyses (label-free LC-MSMS) revealed several clusters of significantly altered proteins in eyes of INSC94Y pigs, indicating a significant role of these molecular networks in DR. Upregulated proteins clustered to interesting canonical pathways in INSC94Y pigs, for example to “role of pi3k subunit p85”, “regulation of actin organization and cell migration”, “RAC1 signaling pathway”, “C-MYC transcriptional activation”, “CDC42 signaling events”, “basic mechanisms of sumoylation” and “calcium Wnt signaling pathway”. In contrast, proteins from molecular pathways “visual signal transduction: rods”, “visual signal transduction: cones”, “endogenous TLR signaling”, “posttranslational regulation of adherens junction stability and disassembly” and “amb2 integrin signaling” were significantly lower abundant in INSC94Y pigs.
This comprehensive molecular phenotyping of a relevant model for human DR offers the unique opportunity to discover novel molecular events driving pathology and potentially novel treatable targets.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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