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Eldon E. Geisert, Justin Templeton, John M. Nickerson, XiangDi Wang, Monica M. Jablonski, Robert W. Williams, Tonia S. Rex; Innate Immune Network in the Retina Activated by Optic Nerve Crush. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6314. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have used a systems biology approach along with microarray technology to identify an innate immune network that is present in the normal retina, activated by optic nerve crush (ONC). This network also plays a role in human disease, glaucoma and age-related macular degeneration (AMD).
Using a recombinant inbred (RI) mouse strain set (BXD, C57BL/6 crosses with DBA/2J mice), we defined genetic networks in the normal mouse retina and genetic networks activated by ONC. The normal dataset is constructed from 80 strains and 326 Illumina microarrays (each with 44,000 probes). The ONC data set (2 days post crush) contains data from 79 strains represented in 234 Illumina microarrays. These massive datasets are hosted by GeneNetwork.org along with a series of powerful bioinformatic tools.
The most novel and exciting network activated by ONC is an innate immune response network. In the ONC Database the top 100 correlates to C4b have correlations above r = 0.8. Some genes within the top 100 include C4b, C3, H2-Q2, H2-Tk23, Cd74, C1q and Cfi. Of the top 500 genes in the C4b network 30 are found in the Retnet database (RetNet.org), and these C4b network genes are associated with retinal disease in humans. For example, many of the genes in the C4b network cause AMD, including C3, EFEMP1, MCDR2, CFB, TLR4, HTA1 and C1QTNF5. The surprising number of human disease genes within the C4b network indicates that this network plays a prominent role in the normal functioning of the retina, for when genes within this network are not functioning normally there is a loss of vision. The evidence suggests that the C4b network as defined by the expression pattern in the 80 BXD RI mouse strains represents an intrinsic network within the retinal cells themselves. In the normal retina, the genes within the network are highly expressed, above the mean expression level for mRNA in the retina. An examination of the network for cellular markers reveals that most of the cell markers are glial markers like Gfap and some are markers for photoreceptor, like Abca4.
Given the genes in the C4b network and their role in injury/disease, it is likely that this network plays a central role in the retina. It is activated by injury including ONC and glaucoma. When members of this network are not functional due to mutation it results in diseases like AMD. This mouse network may open the door to understanding retinal injury and retinal disease.
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