Retinal Mechanisms of Refractive Development

视网膜屈光发育机制

• 批准号: 7582937
• 负责人: Machelle T. Pardue
• 金额: $ 32.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582937
• 关键词: American; Asians; Automobile Driving; Behavior Therapy; Biochemical; Biochemical Feedback; Biochemical Pathway; Blindness; Candidate Disease Gene; Cells; Characteristics; Chickens; Contrast Sensitivity; Country; Data; Defect; Detection; Development; Diagnosis; Dimensions; Dopamine; Down-Regulation; Environment; Epidemic; Eye; Eye Development; Feedback; Frequencies; Genes; Goggles; Growth; Human; Hyperopia; Image; Interferometry; Intervention; Knowledge; Laboratories; Length; Measurement; Measures; Microarray Analysis; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Myopia; Neurons; Operative Surgical Procedures; Optics; Pathway interactions; Photoreceptors; Population; Prevalence; Refractive Errors; Research; Retina; Retinal; Retinal Cone; Retinal Defect; Retinal Detachment; Risk; Role; Signal Pathway; Signal Transduction; Testing; Transducin; Vertebrate Photoreceptors; Vision; Visual; Visual Accommodation; World Health Organization; base; cost; deprivation; design; insight; lens; mouse model; mutant; novel; prevent; programs; public health relevance; research study; response; retinal rods; transmission process; visual deprivation; visual feedback

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.

描述（由申请人提供）：眼睛的产后折射发育与具有轴向长度的光功率匹配，以将视觉图像聚焦到感光体上。成功时，眼睛到达艾米特罗尼亚或零折射率。但是，约25％的美国人口发展近视，而只有10％的远视。在亚洲国家，近视的流行率接近流行病。渐进式近视和高肌层具有增加视网膜脱离和失明的风险。虽然2001年在远程视觉的屈光更正上花费了约39亿美元（不包括进行近100万次屈光手术的成本），但没有治疗以防止或阻止近视的进展。驱动折射发育的机制已定位在视网膜上，但是视网膜途径和生化信号仍然未知。基于以下假设：对比度敏感性和空间频率是驱动此响应的视觉图像的特征，我们假设所涉及的主要视网膜路径是开路和关闭途径。提出了这些途径来刺激抑制默认过度眼睛生长的独特生化信号。因此，正常的折射率依赖于从正常视觉图像激活的视网膜途径中得出的恒定生化反馈。我们进一步假设，视觉环境，视网膜途径或特定的生化信号中的异常将导致生化信号的下调，从而使眼睛生长过多和近视。为了检验这一假设，（AIM 1）在正常和形成剥夺的视觉条件下，将测试特定小鼠模型的特定小鼠模型的折射开发。此外，通过仅使用功能杆或锥体的小鼠，可以测试源自杆或锥形感光器的开或关闭途径可能控制屈光内发育的可能性。折射率的发育将通过测量折射率和眼部维度来评估。与ON和OFF通路相关的生化信号将在AIM 2中研究。我们假设多巴胺是途径信号上的假定。因此，将在ON/OFF途径突变体的折射率发育过程中检查多巴胺的合成和释放，并确定在视网膜特异性多巴胺缺乏小鼠中不存在多巴胺对折射率发育的结果。将使用仅功能性途径的小鼠模型中的基因分析来鉴定OFF途径的生化信号。然后，将在OFF途径突变小鼠中测试候选基因。这些实验旨在确定折射率发育的视网膜机制，从而确定可以防止或阻碍近视发育的药理或行为干预措施的新靶标。公共卫生相关性：未纠正的屈光错误代表了世界上失明的主要原因，并且是世界卫生组织2020年愿景计划的重点。在美国，约有25％的人口患有近视，估计每年花费39亿美元用于屈光远距离视力；不包括每年进行的新处方费用或近100万次屈光手术。拟议的研究将揭示对控制折射发育的视网膜机制的新见解，从而确定新的干预措施的新目标，以防止或阻碍折射率。