Retinal Mechanisms of Refractive Development

出生后眼睛的屈光发育与眼轴长度相匹配，以聚焦视觉 图像传到光感受器上。当成功时，眼睛达到正视或零屈光不正。 然而，大约25%的美国人患有近视，而只有10%的人患有远视。疾病的流行 近视在亚洲国家已经达到了近乎流行的程度。进行性近视和高度近视 会增加视网膜脱离和失明的风险。虽然2001年在以下方面花费了39亿美元 远视力屈光矫正(不包括近100万次屈光手术的费用 手术)，没有预防或阻止近视进展的治疗方法。 驱动屈光发育的机制已经局限于视网膜，但视网膜 通路和生化信号仍不清楚。基于对比度敏感度和 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 视网膜通路包括开通路和离通路。这些途径被认为是为了刺激独特的 抑制默认过度眼球生长的生化信号。因此，正常的屈光发育依赖于 从正常视觉图像激活的视网膜通路中获得持续的生化反馈。我们 进一步假设，视觉环境、视网膜通路或特定生化指标的异常 信号将导致生化信号的下调，从而允许眼睛过度生长和 近视。为了验证这一假说，(目标1)特定小鼠模型的屈光发育 或旁路缺陷将在正常和形觉剥夺的视觉条件下进行测试。此外， 来自视杆或视锥感光器的开或离通路可能控制屈光 开发将通过使用仅具有功能杆或锥体的小鼠进行测试。屈光发育将是 通过测量屈光不正和眼睛尺寸进行评估。与之相关的生化信号 与ON和OFF的通路将在目标2中进行研究。我们假设多巴胺是一个假定的ON 路径信号。因此，将在屈光发育过程中检查多巴胺的合成和释放。 On/Off通路突变体以及缺乏多巴胺对屈光的影响 视网膜特异性多巴胺缺陷小鼠的发育。一个偏离路径的生化信号将是 使用基因图谱在仅具有功能的非通路的小鼠模型中进行鉴定。然后候选基因就会 在非途径突变小鼠身上进行测试。这些实验旨在确定视网膜的机制 屈光发育，从而确定药物或行为干预的新靶点 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.