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Shanu Markand, Paul Wong, Jeffrey H Boatright, J M Nickerson; Interaction between underlying pathways in IRBP induced myopia.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3071.
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© ARVO (1962-2015); The Authors (2016-present)
Myopia is a global public health concern due to increased prevalence and associated with enormous socioeconomic burden. Mechanisms underlying myopia are not fully understood. Studies indicate a complex interplay of genes and environmental factors in myopia development. One of the focuses of our lab is to understand the role of Interphotoreceptor retinoid-binding protein (IRBP, gene RBP3) in myopia development. Mutations in the human RPB3 gene are associated with high myopia and retinal dystrophy. We reported profound myopia and retinal degeneration in the IRBP knockout (KO) mice. In ARVO 2017, we reported that several genes implicated in myopia are differentially regulated in IRBP KO mice (upregulation at P5, decrease at P40 and no change at P213) by droplet digital PCR (ddPCR). In the current project, we examined potential interaction between candidate genes implicated by ddPCR studies. We hypothesize that significant interaction between diverse biological pathways contributes to the myopia phenotype in IRBP KO mice.
Ingenuity pathway analysis was used for network analysis. P-values based on a Fisher’s exact test were tabulated by IPA. A p value <0.05 was considered significant. The resulting interactome was also modified to include indirect interactions that were not in original list of genes.
Most our target genes fitted into a single network indicating significant connection between underlying pathways (Figure). Top functional or disease annotations included development of nervous system (14 molecules, p-value 3.9E-07-3.39E-02), embryonic development (13 molecules, 2.45E-08-3.15E-02), cellular development (11 molecules, 7E-06-3.39E-02) and visual system development and function (7 molecules, 3.9E-07-2.53E-02). Interestingly, some of the signaling pathways such as JNK, MAPK, Insulin and PKC have been implicated in Drosophila organ size determination pathways. These pathways have not been explored in association with myopia development.
Our data support the hypothesis that significant interaction between diverse biological pathways in myopia development in IRBP KO mice. Data analysis uncovered potential novel pathways of myopia previously implicated in Drosophila organ size studies. To validate gene network data, we will examine protein expression of top target genes (Calb1, Isl1, Egr1, Rb1 and Casp3). Future studies will also examine the role of organ size pathways in IRBP induced myopia.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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