Retinal Mechanisms of Refractive Development

出生后，眼睛的屈光发育使屈光力与眼轴长度相匹配，以聚焦视觉 成像到感光器上。当成功时，眼睛达到正视或零屈光不正。 然而，约25%的美国人口发展近视，而只有10%发展远视。之时尚 近视在亚洲国家已达到接近流行病的程度。进行性近视和高度近视 会增加视网膜脱离和失明的风险。2001年，约39亿美元用于 远视力的屈光矫正（不包括近100万次屈光手术的费用 进行），不存在预防或阻止近视进展的治疗。 驱动屈光发展的机制已经局限于视网膜，但视网膜的屈光不正是一个重要的因素。 途径和生化信号传导仍然未知。基于对比敏感度和 空间频率是驱动这种反应的视觉图像的特征，我们假设主要的 所涉及的视网膜通路是ON和OFF通路。这些途径被提议刺激独特的 抑制默认的眼睛过度生长的生化信号。因此，正常的屈光发育依赖于 来自正常视觉图像激活的视网膜通路的恒定生化反馈。我们 进一步假设，视觉环境、视网膜通路或特定生化 信号将导致生物化学信号的下调，这随后允许眼睛过度生长， 近视为了验证这一假设，（目的1）屈光发展的特定小鼠模型与ON 或OFF通路缺陷将在正常和形觉剥夺视觉条件下进行测试。此外该 源自视杆或视锥光感受器的ON或OFF通路可能控制屈光 将通过使用仅具有功能性视杆细胞或视锥细胞的小鼠来测试发育。屈光显影将是 通过测量屈光不正和眼睛尺寸进行评估。相关的生化信号 将在目标2中研究ON和OFF途径。我们假设多巴胺是一个假定的ON 信号通路因此，多巴胺的合成和释放将在屈光发育过程中进行检查， ON/OFF通路突变体以及确定多巴胺缺乏对屈光不正的影响 在视网膜特异性多巴胺缺乏小鼠中的发育。OFF途径生化信号将被 在仅具有功能性OFF途径的小鼠模型中使用基因谱分析鉴定。候选基因将 在OFF途径突变小鼠中进行测试。这些实验旨在确定视网膜机制 屈光发展，从而确定新的药物或行为干预的目标， 可以预防或延缓近视的发展。

Post-natal refractive development of the eye matches optical power with axial length to focus the visual image onto the photoreceptors. When successful, the eye reaches emmetropia or zero refractive error. However, ~25% of the US population develops myopia while only 10% develop hyperopia. The prevalence of myopia has reached near epidemic proportions in Asian countries. Progressive myopes and high myopes have increased risk of retinal detachment and blindness. While ~$3.9 billion dollars was spent in 2001 on refractive corrections for distance vision (not including the cost of nearly 1 million refractive surgeries performed), no treatments exist to prevent or arrest the progression of myopia. The mechanisms driving refractive development have been localized to the retina, but the retinal pathways and biochemical signaling remain unknown. Based on the assumption that contrast sensitivity and spatial frequency are characteristics of the visual image that drive this response, we hypothesize that the main retinal pathways involved are the ON and OFF pathways. These pathways are proposed to stimulate unique biochemical signals that suppress default excessive eye growth. Thus, normal refractive development relies on constant biochemical feedback derived from retinal pathways activated by normal visual images. We further hypothesize that abnormalities in the visual environment, retinal pathways, or specific biochemical signals will result in down-regulation of the biochemical signaling which then allows for excess eye growth and myopia. In order to test this hypothesis, (Aim 1) the refractive development of specific mouse models with ON or OFF pathway defects will be tested under normal and form deprived visual conditions. In addition, the possibility that ON or OFF pathways originating from rod or cone photoreceptors may control refractive development will be tested by using mice with only functional rods or cones. Refractive development will be assessed by measurements of refractive error and ocular dimensions. The biochemical signals associated with the ON and OFF pathway will be investigated in Aim 2. We hypothesize that dopamine is a putative ON pathway signal. Thus, dopamine synthesis and release will be examined during refractive development in the ON/OFF pathway mutants as well as determining the consequence of the absence of dopamine on refractive development in a retina-specific dopamine deficient mouse. An OFF pathway biochemical signal will be identified using gene profiling in a mouse model with only functional OFF pathways. Candidate genes will then be tested in OFF pathway mutant mice. These experiments are designed to determine the retinal mechanisms of refractive development, thus identifying novel targets for pharmacological or behavioral interventions that could prevent or retard the development of myopia.