Atypical opsins and the OIR model of retinopathy of prematurity

摘要 早产儿视网膜病变(ROP)是一种以血管和神经发育异常为特征的视网膜疾病 这会影响接受补充氧疗的早产儿。新生儿护理的进展使 医生拯救越来越多早产儿的生命。然而，这些婴儿面临着极大的风险 发生ROP是因为新生儿保温箱中的高氧水平抑制了视网膜血管的发育。 当回到室内空气中时，会出现代偿性的病理性新生血管，导致视网膜病变。 视网膜神经节细胞视黄素(OPN4)和神经蛋白(OPN5)调节血管发育。 小鼠的围产期。Opn4是一种蓝光敏感的视蛋白，而opn5对可见紫光最敏感 灯。一种依赖于OPN4的光反应通路已被证明可以调节眼睛的血管发育 通过控制VEGFA水平(OPN4-VEGFA途径)(Rao等人，自然，2013；494：243-6)。OPN5还 调节眼睛的血管发育。OPN5基因缺失的小鼠表现出视网膜血管密度轻度升高和 神经元数量和混杂的玻璃体血管回缩(Nguyen等人，自然细胞生物学2019；21：420-429)。 OPN5通过多巴胺调节的VEGFR2表达(OPN5-多巴胺- VEGFR2途径)。这项拟议的研究将检验刺激OPN4-VEGFA蓝的假设 光反应通路将保护氧源性视网膜病变(OIR)的视网膜血管发育 ROP小鼠模型，同时刺激OPN5-多巴胺-VEGFR2紫光通路 加重视网膜病变。为了验证这一创新假设，我们提出了使用鼠标的两个具体目标 OIR模型。在目标1中，我们将探索OPN4操作的作用，检查去除 环境蓝光或增强蓝光对视网膜病变严重程度的影响，同时使用野生型和Opn4 突变的小鼠。在目标2中，我们将探索OPN5操作的作用，检查移除 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 突变的小鼠。蓝光或紫光治疗的效果将在氧疗期间(P7-12)和 随后的发育期(P17-P50)。我们的发现将对产前和新生儿产生广泛的影响。 眼睛护理，并可能导致开发一种创新的、非侵入性的、基于光线的预防性治疗 对于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.