IN VIVO ROLE OF CAVEOLIN-1 IN MODULATING PHOTORECEPTOR FUNCTION

CAVEOLIN-1 在调节光感受器功能中的体内作用

• 批准号: 7720541
• 负责人: MICHAEL R. ELLIOTT
• 金额: $ 21.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720541
• 关键词: Age related macular degeneration; Blood-Retinal Barrier; Caveolae; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Diabetic Retinopathy; Electrodes; Electroretinography; Environment; Extracellular Matrix; Funding; Goals; Grant; Institution; Knockout Mice; Laboratories; Lipids; Oxygen; Pathology; Permeability; Photoreceptors; Phototransduction; Proteins; Research; Research Personnel; Resources; Retinal; Retinal Diseases; Retinal Hemorrhage; Retinopathy of Prematurity; Role; Source; Stress; Suction; Tight Junctions; United States National Institutes of Health; caveolin 1; in vivo; novel; occludin; response; retinal rods

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Loss of the blood-retinal barrier (BRB) is a common pathology of age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity. Evidence from our laboratory indicates that caveolin-1 (Cav-1), an integral protein component of specialized lipid microdomains called caveolae, is essential for normal retinal function. We observed reduced retinal function in Cav-1 null mice as indicated by electroretinography (ERG) suggesting a photoreceptor defect. However, this reduced photoreceptor function cannot be explained by a direct effect on phototransduction as responses were normal in suction electrode recordings from isolated Cav-1 null rods. This has led us to propose that alterations in the local photoreceptor environment results in the observed functional deficit. In support of this hypothesis, we have data demonstrating loss of BRB in Cav-1 null mice and significant changes in the extracellular matrix. The increased permeability correlates with alterations in tight junctions and specifically, occludin localization. Furthermore, when subjected to a stress paradigm (oxygen-induced retinopathy), Cav-1 null mice displayed severe retinal hemorrhaging indicating complete BRB breakdown. These results clearly indicate that Cav-1 expression is essential for BRB integrity. In RPE cells, caveolae display a unique bipolar localization both apically (atypical localization) and basolaterally (typical localization) suggesting potential novel function(s) of caveolar domains in RPE. The goals of this COBRE project are to examine the mechanism(s) by which Cav-1 regulates BRB integrity in the RPE. These goals are aligned with a planned R01 submission and their accomplishment will provide essential data to strengthen this application.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 血视网膜屏障（BRB）丧失是年龄相关性黄斑变性（AMD）、糖尿病性视网膜病变和早产儿视网膜病变的常见病理。我们实验室的证据表明，caveolin-1 (Cav-1) 是一种称为小窝的特殊脂质微结构域的组成部分，对于正常的视网膜功能至关重要。我们观察到 Cav-1 缺失小鼠的视网膜功能降低，视网膜电图 (ERG) 表明存在光感受器缺陷。然而，这种光感受器功能的降低不能用对光转导的直接影响来解释，因为在孤立的 Cav-1 零棒的抽吸电极记录中反应是正常的。这使我们提出，局部光感受器环境的改变会导致观察到的功能缺陷。为了支持这一假设，我们有数据证明 Cav-1 无效小鼠中 BRB 丢失以及细胞外基质发生显着变化。渗透性的增加与紧密连接的改变相关，特别是与occludin定位的改变相关。此外，当受到应激模式（氧诱导的视网膜病变）时，Cav-1缺失小鼠表现出严重的视网膜出血，表明BRB完全崩溃。这些结果清楚地表明 Cav-1 表达对于 BRB 完整性至关重要。在 RPE 细胞中，小凹在顶部（非典型定位）和基底外侧（典型定位）表现出独特的双极定位，表明小凹结构域在 RPE 中具有潜在的新功能。该 COBRE 项目的目标是检查 Cav-1 调节 RPE 中 BRB 完整性的机制。这些目标与计划的 R01 提交一致，它们的实现将为加强此应用程序提供必要的数据。