Retinal Mechanisms of Refractive Development

描述（由申请人提供）：出生后眼睛的屈光发育使屈光力与眼轴长度相匹配，以将视觉图像聚焦到光感受器上。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。近视的流行在亚洲国家已达到接近流行病的比例。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年花费了约39亿美元用于远视力的屈光矫正（不包括进行的近100万次屈光手术的成本），但不存在预防或阻止近视进展的治疗方法。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。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的假设，我们假设所涉及的主要视网膜通路是ON和OFF通路。这些途径被提出来刺激独特的生化信号，抑制默认的眼睛过度生长。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的异常将导致生化信号的下调，从而导致眼睛过度生长和近视。为了检验这一假设，（目的1）将在正常和形觉剥夺视觉条件下测试具有ON或OFF通路缺陷的特定小鼠模型的屈光发育。此外，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源自视杆细胞或视锥细胞的ON或OFF途径可能控制屈光发育的可能性。将通过测量屈光不正和眼部尺寸来评估屈光发育。与ON和OFF通路相关的生化信号将在目标2中研究。我们假设多巴胺是一个假定的ON通路信号。因此，将在ON/OFF途径突变体的屈光发育期间检查多巴胺合成和释放，以及确定在视网膜特异性多巴胺缺陷小鼠中缺乏多巴胺对屈光发育的影响。将在仅具有功能性OFF途径的小鼠模型中使用基因谱分析来鉴定OFF途径生化信号。然后将在OFF途径突变小鼠中测试候选基因。这些实验旨在确定屈光发展的视网膜机制，从而确定可以预防或延缓近视发展的药理学或行为干预的新靶点。公共卫生相关性：未矫正的屈光不正是世界上致盲的主要原因，也是世界卫生组织2020年愿景计划的重点。在美国，约25%的人口患有近视，估计每年花费39亿美元用于远视力的屈光矫正;不包括重新处方的成本或每年进行的近100万次屈光手术。这项拟议的研究将揭示控制屈光发育的视网膜机制的新见解，从而为预防或延缓屈光不正的新干预措施确定新的目标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Uncorrected refractive errors represent the leading cause of blindness in the world and are the focus of the World Health Organization Vision 2020 program. In the US, ~25% of the population has myopia and an estimated $3.9 billion is spent annually for refractive correction of distance vision; not including the cost of renewed prescriptions or the nearly 1 million refractive surgeries that are performed annually. The proposed research will reveal new insights into the retinal mechanisms that control refractive development, thus identifying novel targets for new interventions that would prevent or retard refractive errors.