Atypical opsins and the OIR model of retinopathy of prematurity

摘要 早产儿视网膜病变（Retinopathy of premature，ROP）是一种以血管和神经发育异常为特征的视网膜疾病 影响接受辅助供氧治疗的早产儿。新生儿护理的进步使 医生拯救越来越多的早产儿的生命。然而，这些婴儿有很大的风险， 视网膜母细胞瘤的发生是因为新生儿培养箱中的高氧水平抑制视网膜血管发育。 当返回到室内空气中时，存在导致视网膜病变的代偿性病理性新血管形成。 视网膜神经节细胞视蛋白，黑视蛋白（OPN4）和神经视蛋白（OPN5），调节血管发育， 小鼠围产期。OPN4是蓝光敏感的视蛋白，而OPN5对可见紫光最敏感 光已显示OPN4依赖性光反应途径调节眼睛中的血管发育 通过控制VEGFA水平（OPN4-VEGFA途径）（Rao等，Nature 2013; 494：243 - 6）。OPN5也 调节眼睛中的血管发育。Opn5缺失小鼠显示轻度升高的视网膜血管密度， 神经元数量和混杂的玻璃体血管收缩（Nguyen等，Nature Cell Biol 2019; 21：420 - 429）。 OPN5通过多巴胺调节的VEGFR2表达调节血管发育（OPN5-多巴胺-血管紧张素转换酶抑制剂） VEGFR2途径）。这项研究将验证OPN4-VEGFA蓝刺激 光反应通路将保护氧诱导视网膜病变（OIR）中的视网膜血管发育 ROP小鼠模型，而OPN5-多巴胺-VEGFR2紫光通路的刺激将 加重视网膜病变。为了验证这一创新假设，我们提出了两个具体的目标，使用鼠标 OIR模型。在目的1中，我们将探讨OPN4操纵的作用，检查去除OPN4的影响。 环境蓝光或增强蓝光对视网膜病变严重程度的影响，使用野生型和Opn4 突变小鼠在目标2中，我们将探讨OPN5操纵的作用，检查去除OPN5的影响。 环境紫光或增强紫光对视网膜病变严重程度的影响，使用野生型和Opn5 突变小鼠蓝光或紫光治疗的效果将在氧治疗期间（P7 - 12）和 随后的发育期（P17-P50）。我们的研究结果将对产前和新生儿有广泛的影响 眼睛护理，并可能导致一种创新的，非侵入性的，基于光的预防性治疗的发展 为了ROP。

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.