Transport Processes in Photoreceptors

光感受器中的运输过程

• 批准号: 9195726
• 负责人: YIANNIS KOUTALOS
• 金额: $ 34.27万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-06 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195726
• 关键词: 11 cis Retinal; Acute; Age; Age related macular degeneration; Aldehydes; All-Trans-Retinol; Animals; Binding; Binding Proteins; Blindness; Cytophotometry; Defect; Deposition; Detection; Disease; Dyes; Evaluation; Event; Extracellular Space; Eye; Fluorescence; Fluorescent Dyes; Funding; Generations; Grant; Human; Image; Lead; Light; Link; Lipofuscin; Macular degeneration; Measures; Mediating; Mediation; Microspectrophotometry; Mus; Natural regeneration; Opsin; Pathogenesis; Pathogenicity; Photoreceptors; Photosensitization; Photosensitizing Agents; Physiological; Play; Process; Recovery; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Pigments; Retinoids; Retinol dehydrogenase; Rhodopsin; Rod Outer Segments; Role; Serum Albumin; Source; Structure of retinal pigment epithelium; Testing; Transport Process; Treatment-related toxicity; Vision; Visual; Wild Type Mouse; Work; adduct; chromophore; early onset; effectiveness measure; experimental study; extracellular; fluorescence imaging; insight; interstitial retinol-binding protein; lipophilicity; oxidation; oxidative damage; prevent; public health relevance; retinal damage; retinal rods

DESCRIPTION (provided by applicant): We have recently showed that 11-cis retinal, the light-detecting chromophore of the visual pigment, is a major source of the toxic deposits that originate in the photoreceptors and accumulate in the Retinal Pigment Epithelium in the form of lipofuscin. This work was carried out with mice, and we now propose to extend these studies to the human. Our finding indicates that 11-cis retinal may play a major role in events resulting in retinal degenerations. Defects of retinoid processing in the eye have long been linked to diseases of the retina, but most pathogenic mechanisms have been hitherto associated with either lack of 11-cis retinal or accumulation of its photoproduct all-trans retinal. Here we propos to examine the damage to the human retina initiated by 11-cis retinal. This is particularly important for the human retina, where rhodopsin regeneration is rapid, requiring high fluxes of 11-cis retinal. We will investigate the damage mediated by 11-cis retinal in single living rod photoreceptors from human donor eyes. Mouse rods will be used for comparison, in order to aid in the extrapolation of results from whole animal studies with mice to the human situation. We will use fluorescence imaging of single photoreceptors to measure oxidative damage and the formation of lipofuscin precursors. To determine the relation between the flux of 11-cis retinal and the rate of rhodopsin regeneration, we will measure rhodopsin levels with microspectrophotometry. The aims of the research are: Specific Aim #1: Test if sequestration of 11-cis retinal prevents damage to the rod outer segment. Specific Aim #2: Test if increases in the 11-cis retinal flux increase damage to the rod outer segment. Results from these studies will provide new insights into the basic pathogenic mechanisms underlying vision loss in diseases like Age-Related Macular Degeneration and Stargardt, and suggest possible pathogenic mechanisms for a host of other diseases that might involve the generation and delivery of 11-cis retinal. They will elucidate the process of rhodopsin regeneration, which is essential for the recovery of visual sensitivity after light exposure. By using living human rod photoreceptors, the experimental approach is uniquely able to obtain mechanistic information about the origins of lipofuscin and the process of rhodopsin regeneration in the human eye. These studies will allow the evaluation of the potential toxicity of therapies for 11-cis retinal deficiencies that depend on boosting the chromophore supply. They will also provide a measure for the effectiveness of the opposite type of therapies, which aim to limit lipofuscin formation by slowing down the generation of 11-cis retinal.

描述（由申请人提供）：我们最近表明，视觉颜料的光检测的发色团11-Cis视网膜是源自光感受器并积聚在脂肪素形式的视网膜色素上皮中的有毒沉积物的主要来源。这项工作是用小鼠进行的，我们现在建议将这些研究扩展到人类。我们的发现表明，11盘视网膜可能在导致视网膜变性的事件中起主要作用。长期以来，眼类视黄素处理的缺陷与视网膜的疾病有关，但是大多数致病机制迄今与缺乏11盘视网膜或其光生全型视网膜的积累相关的。在这里，我们提出要检查11张视网膜引发的人类视网膜的损害。这对于人类视网膜尤其重要，在人类视网膜上，在敏捷蛋白的再生迅速，需要高通量为11 cis视网膜。 我们将研究由人类捐赠者眼中的单活棒感光器中11盘视网膜介导的损伤。小鼠杆将用于比较，以帮助推断小鼠整个动物研究的结果到人类情况。我们将使用单个光感受器的荧光成像来测量氧化损伤和脂肪霉素前体的形成。为了确定11张视网膜的通量与视紫红质再生速率之间的关系，我们将用微光照射测定法测量视紫红质水平。 该研究的目的是：特定目标＃1：测试11-CIS视网膜的隔离是否可以防止杆外段损坏。具体目标＃2：测试11-cis视网膜通量的增加是否会增加对杆外部段的损害。 这些研究的结果将为与年龄相关的黄斑变性和Stargardt等疾病中的基本病原机制提供新的见解，并提出可能涉及11- cis视网膜的生成和递送的许多其他疾病的可能的致病机制。他们将阐明视紫红质再生的过程，这对于在暴露后恢复视觉敏感性至关重要。通过使用活着的人杆感光体，实验方法具有独特的能力，能够获得有关脂肪霉素起源和人眼中的视紫红质再生过程的机械信息。这些研究将允许评估疗法的潜在毒性，以依靠增强发色团供应的11盘视网膜缺陷。他们还将为相反类型的疗法的有效性提供措施，旨在限制脂肪霉素形成 减慢了11盘视网膜的产生。