Atypical opsins and the OIR model of retinopathy of prematurity

点击翻译按钮获取中文摘要

Abstract Retinopathy of prematurity (ROP) is a retinal disease characterized by aberrant vascular and neural development that affects prematurely born infants receiving supplemental oxygen therapy. Advances in neonatal care enable physicians to save the lives of increasingly premature infants. However, these infants are at great risk for developing ROP because the high oxygen levels in neonatal incubators suppress retinal vascular development. When returned to room air, there is a compensatory pathological neovascularization that results in retinopathy. Retinal ganglion cell opsins, melanopsin (OPN4) and neuropsin (OPN5), regulate vascular development in the perinatal period of mice. OPN4 is a blue light-sensitive opsin, while OPN5 is maximally sensitive to visible violet light. An OPN4-dependent light response pathway has been shown to regulate vascular development in the eye by keeping VEGFA levels in check (OPN4-VEGFA pathway) (Rao et al., Nature 2013; 494:243-6). OPN5 also regulates vascular development in the eye. Opn5 null mice show mildly elevated retinal vascular density and neuron number, and promiscuous hyaloid vessel retraction (Nguyen et al., Nature Cell Biol 2019; 21:420-429). OPN5 modulates vascular development via dopamine-regulated VEGFR2 expression (OPN5-dopamine- VEGFR2 pathway). The proposed research will test the hypothesis that stimulation of the OPN4-VEGFA blue light response pathway will protect retinal vascular development in an oxygen-induced retinopathy (OIR) mouse model of ROP, while stimulation of the OPN5-dopamine-VEGFR2 violet light pathway will exacerbate retinopathy. To test of this innovative hypothesis, we propose two specific aims using the mouse OIR model. In aim 1, we will explore the role of OPN4 manipulation, examining the effects of removing environmental blue light or enhancing blue light on the severity of retinopathy, using both wildtype and Opn4 mutant mice. In aim 2, we will explore the role of OPN5 manipulation, examining the effects of removing environmental violet light or enhancing violet light on the severity of retinopathy, using both wildtype and Opn5 mutant mice. Effects of blue light or violet light therapy will be assessed during oxygen treatment (P7-12) and in the ensuing developmental period (P17-P50). Our findings will have broad implications for prenatal and neonatal eye care, and may lead to the development of an innovative, non-invasive, light-based preventative treatment for ROP.