Retinal Mechanisms of Refractive Development

描述(申请人提供)：出生后眼睛的屈光发育与眼轴长度相匹配，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，大约25%的美国人患有近视，而只有10%的人患有远视。在亚洲国家，近视的流行程度已经接近流行病的程度。进行性近视和高度近视增加了视网膜脱离和失明的风险。虽然2001年在远视力的屈光矫正上花费了大约39亿美元(不包括近100万例屈光手术的费用)，但目前还没有预防或阻止近视进展的治疗方法。屈光发育的机制已局限于视网膜，但视网膜通路和生化信号仍不清楚。基于对比度敏感性和空间频率是驱动这种反应的视觉图像特征的假设，我们假设涉及的主要视网膜通路是开和关通路。这些途径被认为是为了刺激独特的生化信号，从而抑制默认的过度眼球生长。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持续生化反馈。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。为了验证这一假设，(目标1)在正常和形体剥夺的视觉条件下，将测试具有通路上或通路外缺陷的特定小鼠模型的屈光发育。此外，通过使用仅有功能杆或视锥的小鼠，将测试来自视杆或视锥感光细胞的开或离通路可能控制屈光发育的可能性。屈光发育将通过测量屈光不正和眼睛尺寸来评估。与ON和OFF通路相关的生化信号将在目标2中被研究。我们假设多巴胺是一个假定的ON通路信号。因此，我们将检测On/Off通路突变体的屈光发育过程中多巴胺的合成和释放，以及确定视网膜特异性多巴胺缺陷小鼠缺乏多巴胺对屈光发育的影响。在只有功能偏离途径的小鼠模型中，将使用基因图谱来识别偏离途径生化信号。然后，候选基因将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屈光发育的机制，从而确定可以预防或延缓近视发展的药物或行为干预的新靶点。公共卫生相关性：未经矫正的屈光不正是世界上导致失明的主要原因，也是世界卫生组织2020年远景规划的重点。在美国，约25%的人口患有近视，估计每年花费39亿美元用于远视的屈光矫正；这还不包括更新处方或每年进行近100万次屈光手术的费用。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确定新的靶点。

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.