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TJ Hollingsworth, Anand Swaroop, Emily Y Chew, David Ashbrook, William White, Robert Williams, Monica M Jablonski; Elucidating Mouse Models of Retinal Disease Using Systems Genetics and the BXD Family of Mice. Invest. Ophthalmol. Vis. Sci. 2021;62(8):322.
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© ARVO (1962-2015); The Authors (2016-present)
Animal models of human retinal degenerations (RDs) have been of interest to the vision community for decades. Generating high fidelity models has been hit-or-miss and is often dependent upon the disease itself. Of the RDs, age-related macular degeneration (AMD) is one the most elusive phenotypes to mirror due to numerous genetic polymorphisms and environmental factors associated with it. Recently, the BXD family of mice has become a valuable tool for modeling various ocular diseases. This study’s purpose is to apply a systems genetics approach to the BXD mouse family to better model human AMD, providing the vision community with polygenetic pre-clinical models of AMD.
We identified 27 genes associated with human AMD and, of these, 11 have polymorphisms in the BXD family of mice that are predicted to change gene function in a similar manner to that seen in humans. We chose 6 strains of mice with various combinations of the 11 genes with the goal of selecting mice with various presentations of AMD. The 6 BXD strains and C57B/6J controls are aging from 6 to 18 months. Optical coherence tomography (OCT), full field electroretinogram (ERG), funduscopy/fluorescein angiography (FA) and optokinetic nystagmus (OKN) measurements are performed every 3 months. Histological and ultrastructural analyses will be performed upon euthanasia at 18 months.
Preliminary data indicates BXD34 as a possible AMD model due to drusen-like deposits observed by funduscopy along with degeneration near the central retina by OCT. It also exhibits vascular leakage and a loss of both contrast sensitivity and a- and b-wave amplitudes of the ERG. We have excluded the BXD32 and BXD79 strains as plausible AMD models. BXD32 exhibits markedly rapid degeneration similar to recessive retinitis pigmentosa (RP). BXD79 has phenotypes of high blood glucose, obesity, vascular leakage, and early onset retinal degeneration occurring between 6 months and 9 months of age making it a possible model of diabetic retinopathy (DR).
Currently, BXD34 exhibits the most AMD-like phenotype among the 6 strains chosen for characterization by exhibiting drusen-like deposits and both anatomical and physiological declines in retinal health. BXD32 and BXD79 may better serve as spontaneous models of RP and DR, respectively. Further investigation into these strains is necessary to confirm them as true models of the respective diseases.
This is a 2021 ARVO Annual Meeting abstract.
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