Spectral photoprotection of chronic macular photochemical injury

慢性黄斑光化学损伤的光谱光保护

• 批准号: 8149321
• 负责人: Robert F Bonner
• 金额: $ 35.92万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149321
• 关键词: Chronic; Injury; macula; photoprotection; Chronic; Injury; macula; photoprotection

The associations of autofluorescence changes in age-related macular degeneration (AMD) and Stargardts Dystrophy along with new understanding of role of different photochemistries in creation and modification of the fluorescent bisretinoids support the hypothesis that rising steady-state levels of bisretinoids within the RPE and photoreceptors induce chronic stress and cellular injury. Our biophysical model of bisretinoid pathways with age in humans predicts that spectral sunglasses can remove chronic imbalances between the distinct photochemical processes 1)that create bisretinoids in the photoreceptor outer segments and 2) those that detoxify bisretinoids within the RPE lipofuscin. Since rates of bisretinoid production in the human retina are expected to increase with the square of rate of activation of rhodopsin, cumulative exposures to bright daylight should dominate their production. Therefore we proposed that vermilion, rhodopsin-protecting spectral sunglasses should dramatically reduce bisetinoid production while allowing shorter wavelengths to detoxify accumulated lipofsucin. A common alternative hypothesis is that blue-violet light photochemistries within the retina in the presence of higher levels of retinaldehydes and accumulated bisretinoids drive chronic injury to RPE and photoreceptors through the generation and reaction of reactive oxygen species (ROS). To test these alternative hypotheses, we designed bicolored sunglasses in which one eye is provided a vermilion green-blocking filter that specifically protects rhodopsin and the other eye a yellow blue-violet-blocking filter that specifically protects from short-wavelength photochemical injury. When worn whenever in bright sunlight, such sunglasses allow us to compare changes in both eyes in which only spectral irradiance is changed while genetics, physiology and environmental exposures are otherwise the same. We hypothesize that segregation of A2E into lipofuscin granules and prevention of its redistribution into critical membranes is required for RPE health. To make quantitative predictions, we developed a biophysical model using normal values of pupil size, lens transmission, and rod dark adaptation time constant (trh) to determine average retinal spectral irradiance, steady-state concentration of all-trans-retinal, all-trans-retinal photosensitization of oxidative damage, all-trans-retinal reactions to form A2E-related species in the ROS, and A2E photo-oxidation within RPE lipofuscin granules as a function of age and ambient light intensity. Our model predicts a decline of about one third in the action spectra-weighted short-wavelength macular irradiance with each decade and a nearly constant production rate of A2E-related fluorophores in the RPE during the first 60 years (falling significantly thereafter). A similar age dependence of total lipofuscin granule volume and total fluorescence per RPE cell was reported recently in human cadaver eyes. Since the rates of lipofuscin increase with age are slower than the rate of decrease in short-wavelength macular irradiance in the phakic eye with age, ROI photosensitization in the RPE should also fall with increasing age. Photo-oxidative stress in the outer retina might arise from the smaller amounts of A2E-related fluorophores in critical membranes outside of safer lipofuscin stores. However, if the RPE/BM complex were the site of photo-oxidative injury driving AMD progression, the magnitude and rate of this oxidative injury would be expected to increase dramatically (not observed) following cataract removal and intraocular lens (IOL) implantation. To explain the relationship between bisretinoids and macular degenerations, we propose a novel hypothesis that singlet oxygen generation by RPE lipofuscin allows the chemical alteration of accumulating A2E, thereby limiting the steady-state levels of A2E (A2Ess) in the RPE, the redistribution of A2E into retinal membranes, and associated A2E chemical toxicity. Singlet oxygen generated photochemically within the lipofuscin granule reacts with its A2E to form A2E epoxides which then chemically react to form the increasingly complex cross-linked molecules within the lipofuscin that have not been characterized. As short-wavelength macular irradiance falls with age, the rate of A2E photo-oxidation falls approximately up to 20-fold, causing A2Ess in the normal phakic eye to increase even as rod bleaching and A2E production decrease. Our theoretical model of macular aging reproduces the normal age dependence of lipofuscin and A2E and provides a primary cytotoxic mechanism in which, once A2E exceeds a cytotoxic threshold concentration in the RPE cell, A2E redistribution into critical membranes causes damage and loss of RPE function with or without additional photo-activation. In our model, the yellowing of the lens with age that distorts the spectral balance between rate of production and rate of photo-oxidation found in normal youth, and allows the A2Ess to rise with age. In Stargardts patients mutations in the ABCA4 flippase leads to >5-fold increased production rates of bisretinoids relative to the rates of our proposed RPE photochemical detoxification that results in cytotoxic levels and visual loss at younger ages. In these patients the higher bisretinoid fluorescence and lower contributions of lens autofluorescence, should make identification of spectrally-induced changes within the bisretinoid pathways easier.

与年龄相关的黄斑变性（AMD）和Stargardts营养不良的自动荧光变化的关联，以及对不同光化学在创建和修饰荧光双素的作用的新了解，支持了RPE和光孔稳定稳态的稳态水平的假设，即在RPE和光孔中的稳态水平上升。我们在人类年龄随年龄的双性素途径的生物物理模型预测，光谱太阳镜可以消除不同光化学过程之间的慢性失衡1）在光感受器外部段中产生双肾上腺素的生物性失衡，而2）那些在RPE Lipofuscin中排毒双氧素。由于预计人视网膜中的双蛋白素产量的速率将随着视紫红质激活速率的正方形而增加，因此累积暴露于明亮的日光，应占主导地位。因此，我们提出，朱红蛋白保护光谱太阳镜应大大减少双乙素的产生，同时使波长较短，从而使累积的脂蛋白排毒。 一个常见的替代假设是，在存在较高水平的视网膜葡萄酒和累积的双骨动物的情况下，视网膜内的蓝紫色光进行了光化学，通过反应性氧（ROS）的产生和反应，将慢性损伤带到RPE和感光体。为了检验这些替代假设，我们设计了双色太阳镜，其中为一只眼睛提供了一种朱红色的绿块过滤器，该过滤器专门保护视紫红质，另一只眼睛是黄色的蓝色紫罗兰屏障过滤器，该过滤器专门保护短波长光化学损伤。当每当在亮阳光下穿时，这些太阳镜都可以比较两只眼睛的变化，在这种情况下，只有光谱辐照度改变，而遗传学，生理和环境暴露却是相同的。 我们假设RPE健康需要将A2E分离为脂肪霉素颗粒，并预防其将其重新分布为关键膜。 To make quantitative predictions, we developed a biophysical model using normal values of pupil size, lens transmission, and rod dark adaptation time constant (trh) to determine average retinal spectral irradiance, steady-state concentration of all-trans-retinal, all-trans-retinal photosensitization of oxidative damage, all-trans-retinal reactions to form A2E-related species in the ROS, and A2E photo-oxidation within RPE脂肪霉素颗粒与年龄和环境光强度的关系。我们的模型预测，每十年的动作光谱加权短波黄斑辐照度的下降约为三分之一，并且在头60年中，RPE中与A2E相关的荧光团的生产率几乎恒定（此后大幅下降）。最近在人尸体眼中报道了总脂肪霉素颗粒体积和每个RPE细胞总荧光的年龄依赖性。由于随着年龄的增长，脂肪霉素随着年龄的增长速度的速度慢，而短波长黄斑辐照度的降低速率随着年龄的增长，RPE的ROI光敏化也应随着年龄的增长而下降。外视网膜中的光氧化应激可能是由于更安全的脂肪蛋白蛋白储存量的关键膜中与A2E相关的荧光团较小的氧化应激。但是，如果RPE/BM复合物是驱动AMD进展的光氧化损伤部位，则该氧化损伤的幅度和速率有望在白内障和眼内透镜（IOL）植入后急剧增加（未观察到）。 为了解释双性恋素和黄斑变性之间的关系，我们提出了一个新的假设，即通过RPE脂肪霉素产生单线氧，允许累积A2E的化学改变A2E，从而限制了RPE中A2E（A2ESS）的稳态水平，将A2E的A2E毒性重新分配到视网膜化的eNtical Embranes和相关的化学症状。脂蛋白颗粒内的光化氧与其A2E反应形成A2E环氧化物，然后化学反应以形成脂肪蛋白中尚未表征的日益复杂的交联分子。随着短波长黄斑辐照的年龄下降，A2E光氧化的速率大约下降到20倍，从而在正常的Phakic Eye中导致A2ESS增加，即使Rod漂白和A2E产生降低也会增加。我们的黄斑衰老理论模型再现了脂肪霉素和A2E的正常年龄依赖性，并提供了一种主要的细胞毒性机制，其中一旦A2E超过RPE细胞的细胞毒性阈值浓度，A2E的A2E将重新分配到关键膜中会导致重新分布中的RPE损坏和不带RPE的损坏，而无需其他照片效果。在我们的模型中，随着年龄的增长，镜头的泛黄扭曲了在正常青年中发现的生产率和光氧化速率之间的光谱平衡，并允许A2ESS随着年龄的增长而上升。在ABCA4 Flippase中的StargardtS患者突变中，相对于我们提出的RPE光化学排毒率，双肾上腺素类动物的生产率提高了> 5倍，导致年轻年龄段的细胞毒性水平和视觉丧失。在这些患者中，较高的双蛋白酶荧光和晶状体自动荧光的贡献较低，应使双切素途径内频谱诱导的变化更加容易。