Retinal Mechanisms of Refractive Development

视网膜屈光发育机制

• 批准号: 9043096
• 负责人: Machelle T. Pardue
• 金额: $ 38.98万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043096
• 关键词: Acute; Animals; Automobile Driving; Biochemical Pathway; Biological Availability; Biometry; Birth; Blindness; Chronic; Complex; Cone; Country; Data; Defect; Development; Dopamine; Dopamine Receptor; Drug Targeting; Environment; Environmental Risk Factor; Exposure to; Eye; Funding; Genetic; Growth; Health; Healthcare; House mice; Human; Incidence; Lead; Life Style; Light; Lighting; Measures; Mediating; Metabolism; Mus; Myopia; Neuromodulator; Outcome; Pathway interactions; Pharmacological Treatment; Photoreceptors; Play; Predisposition; Process; Refractive Errors; Research; Retina; Retinal; Retinal Detachment; Retinal Ganglion Cells; Retinal Photoreceptors; Risk; Role; Signal Pathway; Signal Transduction; Societies; Sunlight; Testing; Therapeutic; Vertebrate Photoreceptors; Vision; Visual; Visual impairment; Wild Type Mouse; World Health Organization; base; clinically relevant; cost; deprivation; design; genetic approach; innovation; insight; lens; melanopsin; monocular; mouse development; mouse model; mutant; prevent; programs; protective effect; receptor; receptor expression; research study; response; retinal rods; signal processing; transmission process

 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.

 描述（由申请人提供）：过去 30 年来，近视的发病率以惊人的速度增加，造成视网膜脱离的风险，并花费数十亿美元用于屈光矫正的医疗保健费用。近视的迅速增加表明环境因素可能起着关键作用。我们提出，近视发病率加快的原因是现代社会人们的中间视生活方式。驱动屈光发育的机制已定位于视网膜，但视网膜通路和生化信号传导仍然未知。我们假设中间视觉照明水平（室内照明）通过刺激改变多巴胺和黑视蛋白信号传导的特定视网膜通路而诱发近视。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）照明水平可减少晶状体引起的近视，而中间光照明会增加晶状体引起的近视偏移。此外，越来越多的动物和人类研究表明强光对近视发展有保护作用。这一假设支持将要测试的三个创新想法：1) 环境照明可能会在处理视觉输入的视网膜信号中建立一种强直、稳定的状态，例如暗视和光照明水平会减缓近视眼的生长，而中视照明会促进近视眼的生长，2) 多巴胺信号传导是这些效应的基础，因此中视照明会产生最低水平的多巴胺 与视觉输入破坏相结合时的生物利用度，以及3）含有黑视蛋白的本质光敏视网膜神经节细胞（ipRGC）可能在明视照明下发出眼睛生长的信号。目标 1 将通过测量在有或没有镜头散焦的不同照明条件下饲养的小鼠的屈光不正和眼部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。目标 2 将使用遗传和药理学方法来检查多巴胺受体和多巴胺代谢，研究每种环境照明下多巴胺调节的作用。目标 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介导每种环境照明下的屈光发育。研究结果将提供关于视杆细胞、视锥细胞和 ipRGC 如何通过多巴胺和黑视蛋白信号传导调节视觉驱动的眼睛生长的新见解。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，同时也提供潜在的治疗药物靶标，以减缓或阻止近视进展。