Myopia: the role of cone opsin mutations & glasses that control axial elongation

描述（由申请人提供）：近视是世界范围内的一个主要问题，在一些亚洲国家，受影响的人数估计高达90%。美国的近视患病率呈上升趋势，从1971-1972年的25%上升到1999-2004年的41.6%，一些缺乏医疗服务的民族，如美洲原住民和阿拉斯加爱斯基摩人，特别容易受到影响。据估计，美国有4000万至5000万患者，每年的治疗费用约为20 - 30亿美元。此外，近视会导致继发性并发症，导致视力严重下降。近视是由遗传和环境因素共同引起的。人类通常天生远视，眼睛太短，看不见光学。在发育过程中，视觉经验调节着眼睛的生长，因此当眼睛的长度达到光学的最佳状态（远视）时，眼睛就会停止生长。当眼睛生长超过远视点，变得太长时，就会发生近视。长(L)和中(M)波长敏感的视锥细胞介导视觉引导的眼睛生长。初步数据表明：1)L和M视锥蛋白基因的罕见变异是严重遗传性近视的基础；2)普通近视与L和M视锥蛋白基因变异之间存在关联；3)L和M视锥蛋白的比例影响视觉引导下的眼睛生长。L和M视蛋白基因是高度可变的，在视蛋白中编码大量的氨基酸序列变异，使它们成为引起常见近视的绝佳候选者。L和M视锥细胞的比例在个体之间也有很大差异，这导致视网膜回路对环境刺激的反应存在差异，进而影响眼睛的生长。L/M视锥色素和视锥比参与调节眼睛生长的机制，表明轴向伸长可以通过改变视觉体验来控制。在一项初步研究中，孩子们戴着一种特殊的眼镜，其中一个是实验镜片，一个是对照镜片，持续三个月。两种镜片都有个人的最佳矫正。实验用的镜片上有一个阻色滤光片来去除红光，还有一个全息漫射器来稍微模糊图像。对照透镜同样通过红光和绿光，但确保两只眼睛在整个研究过程中暴露在相同的光强度下。每隔两周测量一次轴向长度。佩戴实验组晶状体的眼睛生长速度明显慢于佩戴对照组晶状体的眼睛（p=0.001），这是一种非常有前途的预防近视的方法。该应用程序实现了NEI健康差异战略计划的既定目标，即“确定人类近视的病因，并确定与此和其他屈光不正相关的风险因素，以防止其发生或发展。”具体目的1将评估视锥比、视轴长度、L和M视锥蛋白基因变异在近视病因中的作用。目的2将通过比较近视风险人群的视锥比来研究L: M视锥比在近视病因学中的作用。目的3将评估透镜的潜力，以阻止特定波长的光，并引入图像模糊在减缓轴向伸长的近视儿童。

DESCRIPTION (provided by applicant): Myopia is a major problem worldwide with the number of affected individuals estimated to be as high as 90% for some Asian countries. The prevalence of myopia in the US is on the rise, up from 25% in 1971-1972 to 41.6% in1999-2004, with some underserved ethnic groups such as Native Americans and Alaskan Eskimos being particularly susceptible. The annual cost of treatment approximates 2-3 billion dollars for the estimated 40-50 million affected individuals in the US. In addition, myopia can lead to secondary complications that cause severely reduced vision. Myopia is caused both by genetic and environmental factors. Humans are normally born hyperopic, with eyes too short for the optics. During development, visual experience regulates eye growth so that the eye stops growing when the length is optimal for the optics (emmetropia). Myopia occurs when the eye grows past the point of emmetropia, becoming too long. The long- (L) and middle- (M) wavelength-sensitive cones mediate visually guided eye growth. Preliminary data is presented suggesting that 1) rare variants of the L and M cone opsin genes underlie a severe inherited form of myopia 2) there is an association between common myopia and variants of L and M opsin genes and 3) the L to M cone ratio influences visually guided eye growth. The L and M cone opsin genes are highly variable, encoding a tremendous amount of amino acid sequence variation in the opsins, making them excellent candidates for causing common forms of myopia. The ratio of L to M cones is also highly variable across individuals, which produces variability in the response of retinal circuits to environmental stimuli, which in turn influences eye growth. The involvement of the L/M cone pigments and cone ratio in the mechanism regulating eye growth suggests that axial elongation can be controlled by modifying visual experience. In a pilot study, children wore special eyeglasses containing one experimental and one control lens for three months. Both lenses had the individual's optimal correction. The experimental lens had a color-blocking filter to remove red light, and a holographic diffuser to blur the image slightly. The control lens passed red and green light equally but ensured that both eyes were exposed to the same light intensity throughout the study. Axial length measurements were taken at two week intervals. Eyes wearing the experimental treatment lens grew significantly slower than eyes wearing the control lens (p=0.001), making this a very promising method for preventing myopia. This application addresses the stated objective in NEI's Health Disparities Strategic Plan to "determine the etiology of human myopia and identify the risk factors associated with this and other refractive errors so as to prevent their occurrence or progression." Specific aim 1 will evaluate the role of cone ratio, axial length, and L and M cone opsin gene variants in the etiology of myopia. Aim 2 will investigate the role of L: M cone ratio in the etiology of myopia by comparing ratios across ethnic groups particularly at risk for myopia. Aim 3 will evaluate the potential of lenses that block specific wavelengths of light and introduce image blur in slowing axial elongation in myopic children.