Retinal Mechanisms of Refractive Development

 描述（由申请人提供）：近视（近视）的发病率在过去30年中以惊人的速度增加，造成视网膜脱落的风险，并花费数十亿美元用于屈光矫正的医疗保健。近视的快速增加表明环境因素可能起着关键作用。我们认为，近视发病率加速的原因是现代社会人们所共有的中间型生活方式。驱动屈光发展的机制已经定位于视网膜，但视网膜通路和生化信号仍然未知。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，改变多巴胺和黑视素信号转导诱导近视。这一假设得到了试验数据的支持，试验数据显示暗视（夜空）和明视（阳光）照明水平降低了镜片诱导的近视，而中间视觉照明增加了镜片诱导的近视移位。此外，越来越多的动物和人类研究表明，强光对近视发展具有保护作用。这一假设支持三个创新的想法，将进行测试：1）环境照明可以在视网膜信号传导中建立紧张的稳定状态，视觉输入在该状态下被处理，使得暗视和光照明水平减缓近视眼生长，而中间照明促进近视眼生长，（二）多巴胺信号传导是这些效应的基础，破坏的视觉输入，和3）含有黑视蛋白的固有光敏视网膜神经节细胞（ipRGC）可以在明视照明下发出眼睛生长的信号。目的1将通过测量在不同照明条件下（有和没有透镜散焦）饲养的小鼠的屈光不正和眼生物学来检查不同的环境照明水平是否改变对近视的易感性。目的2将研究多巴胺调制的作用下，每一个环境照明使用遗传和药理学的方法来检查多巴胺受体和多巴胺代谢。目的3将通过使用黑视蛋白缺陷小鼠模型来确定黑视蛋白是否在每个环境照明中介导屈光发育。这些结果将为关于视杆细胞、视锥细胞和ipRGC如何通过多巴胺和黑视素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，同时也提供了减缓或阻止近视进展的潜在治疗药物靶点。

 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.