Retinal Mechanisms of Refractive Development

 描述(由申请人提供)：在过去的30年里，近视(近视)的发病率以惊人的速度增加，造成了视网膜脱离的风险，并花费了数十亿美元的医疗费用进行屈光矫正。近视的迅速增加表明环境因素可能起到关键作用。我们认为近视发病率加快的原因是现代社会人们共同的中间视觉生活方式。屈光发育的机制已局限于视网膜，但视网膜通路和生化信号仍不清楚。我们假设，中间视觉照明水平(室内照明)通过刺激特定的视网膜通路来诱导近视，这些通路改变了多巴胺和黑色素信号。这一假设得到了试点数据的支持，该数据显示，暗视(夜空)和明视(阳光)照明水平减少了晶状体诱导的近视，而中间视觉照明增加了晶状体诱导的近视偏移。此外，越来越多的动物和人体研究表明，强光对近视发展具有保护作用。这一假说支持三个将接受检验的创新想法：1)环境照明可在视网膜信号中建立一种紧张性的、稳定的状态，视觉输入据此进行处理，如暗视和光照明水平减缓近视眼睛的生长，而中间视觉照明促进近视眼睛生长；2)多巴胺信号是这些效应的基础，因此当中间视觉照明与中断的视觉输入相结合时，中间视觉照明产生最低水平的多巴胺生物利用度；以及3)含有黑素的固有光敏视网膜神经节细胞(IpRGC)可能在明视照明下信号眼睛生长。目标1将通过测量在不同照明条件下有和没有透镜离焦的小鼠的屈光不正和眼生物测量来检查不同的环境照明水平是否会改变近视的易感性。目的2将利用遗传和药理学方法检测多巴胺受体和多巴胺代谢，研究在每种环境照明下多巴胺调节的作用。目标3将通过使用黑色素缺乏的小鼠模型来确定黑色素是否在每种环境照明下调节屈光发育。这一结果将为视杆细胞、视锥细胞和ipRGC如何通过多巴胺和黑素蛋白信号调节视觉驱动的眼睛生长提供新的见解。这些实验将确定可能改变近视易感性的临床相关环境因素，同时还将提供潜在的治疗药物靶点，以减缓或阻止近视进展。

 DESCRIPTION (provided by applicant): The incidence of myopia (near-sightedness) has increased in alarming rates over the last 30 years, creating the risk for retinal detachment and costing billions in healthcare dollars for refractive corrections. The rapid increase in myopia suggests that environmental factors may play a key role. We propose that the reason for the accelerating incidence of myopia is the mesopic lifestyle shared by people in modern society. The mechanism driving refractive development has been localized to the retina, but the retinal pathways and biochemical signaling remain unknown. We hypothesize that mesopic illumination levels (indoor lighting) induce myopia by stimulating specific retinal pathways which alter dopamine and melanopsin signaling. This hypothesis is supported by pilot data that shows that scotopic (night sky) and photopic (sunlight) illumination levels reduce lens-induced myopia, while mesopic illumination increases lens-induced myopic shifts. Additionally, a growing number of animal and human studies show protective effects of bright light on myopia development. This hypothesis supports three innovative ideas that will be tested: 1) ambient lighting may establish a tonic, steady state in retinal signaling upon which visual input is processed, such tha scotopic and photoic illumination levels slow myopic eye growth and mesopic illumination promotes myopic eye growth, 2) dopamine signaling underlies these effects such that mesopic illumination produces the lowest level of dopamine bioavailability when combined with disrupted visual input, and 3) melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) may signal eye growth under photopic illumination. Aim 1 will examine whether different ambient illumination levels alter susceptibility to myopia by measuring refractive error and ocular biometry of mice housed under different lighting conditions with and without lens defocus. Aim 2 will investigate the role of dopamine modulation under each ambient illumination using genetic and pharmacological approaches to examining dopamine receptors and dopamine metabolism. Aim 3 will determine whether melanopsin mediates refractive development in each ambient illumination by using melanopsin-deficient mouse models. The results will provide new insights about how rods, cones and ipRGCs regulate visually-driven eye growth through dopamine and melanopsin signaling. These experiments will identify clinically relevant environmental factors that may alter susceptibility to myopia while also providing potential therapeutic drug targets to slow or stop myopia progression.