Pigment Regeneration Mechanisms in the Human Retina

人类视网膜色素再生机制

• 批准号: 10259840
• 负责人: Frans Vinberg
• 金额: $ 38.39万
• 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/10259840
• 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; Regenerative pathway; Research; Retina; Retinal Cone; Retinal Pigments; Retinal macula; Rod; Rodent; Role; Salamander; Sampling; Strategic Planning; Structure of retinal pigment epithelium; Suction; Sunlight; Techniques; Testing; 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年中 使用小鼠作为模型系统的哺乳动物棒和锥形感受器中的适应性以及疾病。 但是，小鼠是一种缺乏黄斑的夜间动物，黄斑是灵长类动物视网膜中的专门中央区域 这为人类每天生存至关重要的高品质色觉提供。因此，人类的机制 白天视觉或破坏黄斑中光感受器的疾病，例如与年龄相关的黄斑 退化（AMD）在小鼠中挑战。例如，干燥没有有效的治疗方法 AMD的形式，是古老的失明原因。那是迫切需要更好的 了解人类黄斑在健康和疾病中感光细胞的生物学。这尤其正确 与已经进行了更广泛研究的棒相比，锥形感受器的圆锥体光感受器。最近的研究 在小鼠视网膜内建立了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Müller细胞再生色素 途径（独立于光和依赖性的视图内视觉循环）或感光细胞本身 通过细胞自主再生机制。但是，对这些机制中的这些机制一无所知 人黄斑或中央凹。该提案的目的是确定独立于RPE的贡献 颜料再生途径，通往锥体的能力，快速适应黑暗并在明亮的光线下保持灵敏度 特别是在人类黄斑中。我们的中心假设是通过 RPE太慢，无法在明亮的光线下保持视力或在快速变化的水平中介导黑暗适应 人类黄斑中的照明。这项工作分为两个具体的目标。这些是要确定 光独立视觉周期（AIM I）和光色素再生途径的贡献 （AIM II）对人黄斑锥的光灵敏度的黑暗适应和维持。实验会 使用离体电视图和单细胞惊喜电极记录。这些技术很好 适合评估黑暗中视觉周期和细胞自主色素再生途径的作用 光灵敏度的适应和维持。我们将利用我们的经验和合作 在过去三年中，我们建立了眼库，以制定捐助者标准和协议 记录器官或研究供体人类眼睛1 - 5小时的黄斑锥的光诱发反应 验尸。这些研究的结果将确定不同的视觉周期途径对人的贡献 视觉由视网膜地理区域的圆锥体介导，包括中央凹。这些信息将 为阐明黄斑营养不良的发病机理和潜在靶标的研究提供了基础 视力或防止衰老或患病的人眼视力丧失。