Pigment Regeneration Mechanisms in the Human Retina

人类视网膜色素再生机制

• 批准号: 10033250
• 负责人: Frans Vinberg
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033250
• 关键词: Affect; Age; Age related macular degeneration; Aging; Animal Model; Animals; Automobile Driving; Autopsy; Biochemical Reaction; Biological Models; Biology; Blindness; Cells; Collaborations; Color Visions; Cone; Critical Pathways; Dark Adaptation; Darkness; Disease; Elderly; Electrodes; Electrophysiology (science); Electroretinography; Environment; Eye; Eye Banks; Face; Geographic Locations; Goals; Health; Hour; Human; Individual; Kinetics; Knowledge; Light; Light Adaptations; Lighting; Maintenance; Measures; Mediating; Methods; Molecular; Muller' s cell; Mus; National Eye Institute; Natural regeneration; Neural Retina; Organ; Organ Donor; Panthera leo; Pathogenesis; Pathway interactions; Peripheral; Photons; Photophobia; Photoreceptors; Pigment Epithelium; Pigments; Primates; Process; Protocols documentation; Reading; Research; Retina; Retinal Cone; Retinal Pigments; Retinal macula; Rod; Rodent; Role; Salamander; Sampling; Strategic Planning; Structure of retinal pigment epithelium; Suction; Techniques; Testing; The Sun; Time; Tissue Donors; Tissues; Transportation; Utah; Vision; Vision research; Work; base; disorder of macula of retina; effective therapy; experience; experimental study; fovea centralis; human disease; improved; insight; macula; macular dystrophy; nonhuman primate; prevent; response; retinal rods; tissue preparation; visual cycle

ABSTRACT During the past 2-3 decades important work has been done to resolve the mechanisms of light and dark adaptation as well as disease in the mammalian rod and cone photoreceptors using mouse as a model system. However, the mouse is a nocturnal animal that lacks the macula, a specialized central region in primate retina that provides high-acuity color vision critical for human everyday survival. Consequently, mechanisms of human daytime vision or diseases that disrupt photoreceptors in the macula, such as Age-Related Macular Degeneration (AMD), are challenging to study in mice. For example, there is no effective treatment for the dry form of AMD, the most common cause of blindness among the elderly. Thus, there is a critical need to better understand the biology of the photoreceptors in the human macula in health and disease. This is particularly true of cone photoreceptors compared to rods that have been more extensively studied. Recent studies have established both light-independent and light-dependent pigment regeneration pathways within the mouse retina isolated from the pigment epithelium (RPE). These pathways regenerate pigment via Müller cells in cone-specific pathways (light-independent and -dependent intraretinal visual cycles) or in the photoreceptor cells themselves by a cell-autonomous regeneration mechanism. However, nothing is known about these mechanisms in the human macula or fovea. The goal of this proposal is to determine the contribution of the RPE-independent pigment regeneration pathways to the ability of cones to dark adapt quickly and maintain sensitivity in bright light specifically in the human macula. Our central hypothesis is that the canonical visual cycle that operates via the RPE is too slow to maintain vision in bright light or mediate dark adaptation during rapidly changing levels of illumination in the human macula. The work is organized into two specific aims. These are to determine the contribution of the light-independent intraretinal visual cycle (Aim I) and photic pigment regeneration pathways (Aim II) to dark adaptation and maintenance of light sensitivity of human macular cones. The experiments will employ ex vivo electroretinography and single cell suction electrode recordings. These techniques are well suited for assessing the role of visual cycles and cell-autonomous pigment regeneration pathways in dark adaptation and maintenance of light sensitivity, respectively. We will leverage our experience and collaborations with Eye Banks that we have established during the past three years to develop donor criteria and protocols to record light-evoked responses of macular cones from organ or research donor human eyes 1 – 5 hours postmortem. Results of these studies will determine the contribution of different visual cycle pathways to human vision mediated by the cones across geographical regions of the retina, including the fovea. This information will provide a basis for studies to elucidate pathogenesis of macular dystrophies and potential targets to improve vision or prevent vision loss in aging or diseased human eye.

抽象的 在过去的2-3年里，人们在解决光与暗的机制方面做了重要的工作。 使用小鼠作为模型系统，研究哺乳动物视杆细胞和视锥细胞光感受器的适应和疾病。 然而，老鼠是一种夜行动物，缺乏黄斑，这是灵长类动物视网膜的一个特殊的中心区域 它提供了对人类日常生存至关重要的高敏锐度色觉，这是人类的机制。 日间视力或破坏黄斑感光细胞的疾病，例如年龄相关性黄斑 变性（AMD）在小鼠身上的研究具有挑战性，例如，没有有效的治疗方法。 AMD 是导致老年人失明的最常见原因，因此迫切需要更好的治疗方法。 了解人类黄斑中光感受器在健康和疾病中的生物学特性尤其如此。 最近的研究已经对视锥细胞与视杆细胞的比较进行了更广泛的研究。 在小鼠视网膜内建立了光独立和光依赖性色素再生途径 从色素上皮 (RPE) 中分离出来，这些途径通过锥体特异性的穆勒细胞再生色素。 通路（光独立和依赖的视网膜内视觉周期）或感光细胞本身 然而，人们对这些机制一无所知。 该提案的目标是确定与 RPE 无关的贡献。 色素再生途径使视锥细胞能够快速适应黑暗并在亮光下保持敏感度 特别是在人类黄斑中，我们的中心假设是规范的视觉循环通过 RPE 太慢，无法在强光下维持视力，也无法在快速变化的光线水平下介导暗适应。 这项工作分为两个具体目标。 光独立的视网膜内视觉周期（Aim I）和光色素再生途径的贡献 （目标二）人类黄斑锥体的暗适应和光敏感性的维持。 采用离体视网膜电图和单细胞抽吸电极记录这些技术很好。 适用于评估黑暗中视觉周期和细胞自主色素再生途径的作用 我们将分别利用我们的经验和合作来适应和维持光敏感性。 与我们在过去三年中建立的眼库一起制定捐赠标准和协议 记录来自器官或研究供体人眼的黄斑锥体的光诱发反应 1 – 5 小时 这些研究的结果将确定不同视觉周期通路对人类的贡献。 视觉由视网膜上的视锥细胞（包括中央凹）介导。 为阐明黄斑营养不良的发病机制和改善黄斑营养不良的潜在目标提供研究基础 视力或防止老化或患病的人眼视力丧失。