IRBP is expressed much earlier than needed for any putative role in the visual cycle. In the previous grant cycle, we showed that IRBP is needed in early retina development, as without it we detected morphological changes coincident with terminal differentiation of rods and cones, and precocious development of the outer plexiform layer. At the same time, we discovered excessive eye growth and elongation of the optical axis starting distinctly at P7. This implies a role for IRBP in controlling eye growth even without vision-based signaling. We now know that IRBP loss causes diverse and severe eye diseases including profound myopia and retinal degeneration, and we recently discovered sluggish pupillary light reflexes (PLRs). In recent human GWAS studies, IRBP polymorphisms are associated with refractive error and corneal curvature. Previous linkage studies established that IRBP defects caused combined RP and severe myopia. We view abnormalities of IRBP deficiency in the context of eye disease that affect normal determination of eye size, based on strong and abundant previous and concurrent work in developmental biology of the Drosophila eye and organ size fate. We test the same five principal pathways that regulate size determination in the IRBP knockout eye. We seek to understand posited hierarchical relationships among myopia, RD, and other abnormalities in IRBP mutations. To do that we have constructed and validated a new conditional knockout (KO) mouse and a new traditional KO. Here we use them to sort out the temporal, spatial, and mechanistic relationships that cause these three major symptoms. Last, we test efficacy of drugs known to slow myopia or organ size, in the IRBP-/- model asking if they are effective in reducing any or all IRBP deficiency symptoms.
We know that IRBP loss causes diverse and severe eye diseases including profound myopia, retinal degeneration, and other symptoms. In this project, the two Aims are to discover the mechanisms and pathways damaged by the absence of IRBP resulting in the observed pathology. We seek to understand the hierarchical or networked relationships among gene regulatory and biochemical pathways that lead to these debilitating symptoms, with the intent of testing drug targets to alleviate these symptoms.
| Liu, Yi-Hsia; Corbett, Clare; Klaska, Izabela P et al. (2018) Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3). Exp Eye Res 172:54-65 |
| Wang, Jiaxing; Struebing, Felix L; Ferdous, Salma et al. (2018) Differential Exon Expression in a Large Family of Retinal Genes Is Regulated by a Single Trans Locus. Adv Exp Med Biol 1074:413-420 |
| Henneman, Nathaniel F; Foster, Stephanie L; Chrenek, Micah A et al. (2018) Xanthohumol Protects Morphology and Function in a Mouse Model of Retinal Degeneration. Invest Ophthalmol Vis Sci 59:45-53 |
| Gooding, Sarah W; Chrenek, Micah A; Ferdous, Salma et al. (2018) Set screw homogenization of murine ocular tissue, including the whole eye. Mol Vis 24:690-699 |
| Chrenek, Micah A; Nickerson, John M; Boatright, Jeffrey H (2016) Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease. Asia Pac J Ophthalmol (Phila) 5:304-8 |
| Schmidt, Robin H; Nickerson, John M; Boatright, Jeffrey H (2016) Exercise as Gene Therapy: BDNF and DNA Damage Repair. Asia Pac J Ophthalmol (Phila) 5:309-11 |
| Bhatia, Shagun K; Rashid, Alia; Chrenek, Micah A et al. (2016) Analysis of RPE morphometry in human eyes. Mol Vis 22:898-916 |
| Rashid, Alia; Bhatia, Shagun K; Mazzitello, Karina I et al. (2016) RPE Cell and Sheet Properties in Normal and Diseased Eyes. Adv Exp Med Biol 854:757-63 |
| Markand, Shanu; Baskin, Natecia L; Chakraborty, Ranjay et al. (2016) IRBP deficiency permits precocious ocular development and myopia. Mol Vis 22:1291-1308 |
| Grossniklaus, Hans E; Geisert, Eldon E; Nickerson, John M (2015) Introduction to the Retina. Prog Mol Biol Transl Sci 134:383-96 |
Showing the most recent 10 out of 20 publications
