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.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 血-视网膜屏障（BRB）的丧失是年龄相关性黄斑变性（AMD）、糖尿病视网膜病变和早产儿视网膜病变的常见病理。来自我们实验室的证据表明，小窝蛋白-1（Cav-1），一种称为小窝的专门脂质微结构域的组成蛋白，对正常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，如视网膜电图（ERG）所示，表明感光细胞缺陷。然而，这种减少的感光功能不能解释的直接影响光转导的反应是正常的吸力电极记录从孤立的Cav-1空杆。这使我们提出，在当地的感光环境的变化导致观察到的功能缺陷。为了支持这一假设，我们有数据表明Cav-1基因敲除小鼠中BRB的丢失和细胞外基质的显著变化。增加的渗透性与紧密连接的改变相关，特别是occludin定位。此外，当经受应激范例（氧诱导的视网膜病变）时，Cav-1缺失小鼠显示出严重的视网膜变性，表明BRB完全崩溃。这些结果清楚地表明，Cav-1的表达是必不可少的BRB的完整性。在RPE细胞中，小窝在顶部（非典型定位）和基底外侧（典型定位）均显示出独特的双极定位，这表明小窝结构域在RPE中具有潜在的新功能。这个COBRE项目的目标是研究Cav-1调节RPE中BRB完整性的机制。这些目标与计划的R 01提交保持一致，其实现将为加强该应用提供必要的数据。