Retinal Mechanisms of Refractive Development

描述（由申请人提供）：出生后眼睛的屈光发育将光功率与轴长相匹配，以将视觉图像聚焦到光感受器上。成功后，眼睛达到远视或零屈光不正。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，近视的发病率已接近流行病的程度。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，用于远距离视力的屈光矫正花费约39亿美元（不包括近100万例屈光手术的费用），但没有任何治疗方法可以预防或阻止近视的发展。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不清楚。基于对比敏感度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on和OFF通路。这些途径被认为是刺激独特的生化信号，抑制默认的过度眼睛生长。因此，正常的屈光发育依赖于由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，（目的1）将在正常和形式剥夺的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，来自杆状或锥状光感受器的ON或OFF通路可能控制屈光发育的可能性将通过仅具有功能的杆状或锥状细胞的小鼠进行测试。屈光发展将通过测量屈光不正和眼尺寸来评估。与ON和OFF通路相关的生化信号将在Aim 2中进行研究。我们假设多巴胺是一种假定的ON通路信号。因此，多巴胺的合成和释放将在ON/OFF通路突变体的屈光发育过程中进行研究，并确定在视网膜特异性多巴胺缺陷小鼠中多巴胺缺乏对屈光发育的影响。一个OFF通路生化信号将在一个只有功能性OFF通路的小鼠模型中使用基因谱来识别。候选基因随后将在OFF通路突变小鼠中进行测试。这些实验旨在确定屈光发育的视网膜机制，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，每年用于远距离视力屈光矫正的费用估计为39亿美元；这还不包括更新处方的费用，也不包括每年近100万例屈光手术的费用。这项研究将揭示控制屈光发展的视网膜机制的新见解，从而确定预防或延缓屈光不正的新干预措施的新目标。

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.