Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity

Caveolin-1 在维持血视网膜屏障完整性中的作用

基本信息

批准号：
7783730
负责人：
MICHAEL H ELLIOTT
金额：
$ 37.28万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7783730
关键词：
ATP phosphohydrolase Adhesions Adhesiveness Adult Affect Affinity Age related macular degeneration Apical Binding Blindness Blood Vessels Blood-Retinal Barrier Buffers Caveolae Cells Cholesterol Data Defect Diabetic Retinopathy Edema Electroretinography Environment Epithelial Epithelial Cells Fractionation Frameshift Mutation Genetic Homeostasis Human Integral Membrane Protein Ion Transport Ions Knockout Mice Lactate Transporter Ligands Lipids Maintenance Measures Membrane Mus Na(+)-K(+)-Exchanging ATPase Neural Retina Organelles Oxygen Pathology Permeability Phenotype Phosphorylation Photoreceptors Phototransduction Play Process Proteins Regulation Retina Retinal Retinal Degeneration Retinal Diseases Retinal Edemas Retinal Hemorrhage Retinal Pigments Retinopathy of Prematurity Role Signal Transduction Stress Structure Structure of retinal pigment epithelium Testing Therapeutic Tight Junctions Transgenic Mice Transmembrane Transport age related basolateral membrane caveolin 1 cell type cellular microvillus cholesterol trafficking design in vivo in vivo Model novel occludin potassium ion public health relevance recombinase response retinal rods

项目摘要

DESCRIPTION (provided by applicant): The blood-retinal barrier (BRB) selectively and tightly regulates the local environment of the neural retina. Loss of BRB integrity is a common pathology in three major causes of blindness: diabetic retinopathy; age- related macular degeneration; and retinopathy of prematurity. Recent evidence indicates that caveolin-1 (Cav- 1), an integral protein component of specialized lipid micro-domains called caveolae, is essential for normal retinal function. Cav-1 null mice display reduced retinal function in Cav-1 null mice as indicated by electroretinography (ERG) that suggested at a photoreceptor defect. However, this reduced photoreceptor function could not be explained by a direct effect on phototransduction as responses were normal in recordings from isolated Cav-1 null rods. This suggests that the functional deficit in Cav-1 null retinas results from an abnormal local environment surrounding photoreceptors. In support of this hypothesis, compelling evidence indicates that Cav-1 null mice have a hyper-permeable BRB. The increased permeability correlates with alterations in tight junctions, changes in Na/K-ATPase activity, and outer retinal edema. Cav-1 null mice provide compelling data showing a clear loss of retinal pigment epithelial and vascular barrier functions. This increased permeability alters the normal photoreceptor environment which is consistent with reduced retinal function and age-related retinal degeneration observed in these mice. Furthermore, when subjected to a stress paradigm (oxygen-induced retinopathy), Cav-1 null mice display severe sub-retinal and intra-retinal hemorrhaging. These findings clearly indicate that Cav-1 expression/function is essential for the maintenance of a robust BRB but the mechanism(s) of this regulation is unknown. The first aim is designed to determine the role of Cav-1 in regulating barrier activity specifically within the retinal pigment epithelium using cell-specific, inducible genetic deletion. The second aim will test the role of Cav-1 in the structural organization of lipids and proteins in epithelial cell-cell contacts and apical process. The final aim will focus on the role that dysregulation of the Na/K-ATPase plays and how Cav-1 regulates ATPase activity. PUBLIC HEALTH RELEVANCE: Loss of blood-retinal barrier integrity is a common pathology in three major causes of blindness: diabetic retinopathy; age-related macular degeneration; and retinopathy of prematurity. This project is designed to study mechanisms that regulate blood-retinal barrier integrity to define novel potential therapeutic strategies to ameliorate pathological blood-retinal barrier permeability.

描述（申请人提供）：血视网膜屏障（BRB）选择性且严格地调节神经视网膜的局部环境。 BRB 完整性丧失是导致失明的三种主要原因的常见病理：糖尿病性视网膜病变；年龄相关性黄斑变性；和早产儿视网膜病变。最近的证据表明，caveolin-1 (Cav-1) 是一种称为小窝的特殊脂质微结构域的完整蛋白质成分，对于正常的视网膜功能至关重要。视网膜电图 (ERG) 表明，Cav-1 缺失小鼠的视网膜功能降低，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 空棒的记录中反应是正常的。这表明 Cav-1 无效视网膜的功能缺陷是由于光感受器周围的局部环境异常造成的。为了支持这一假设，令人信服的证据表明 Cav-1 缺失小鼠具有高渗透性 BRB。通透性增加与紧密连接的改变、Na/K-ATP酶活性的变化和外视网膜水肿相关。 Cav-1缺失小鼠提供了令人信服的数据，显示视网膜色素上皮和血管屏障功能明显丧失。这种增加的通透性改变了正常的光感受器环境，这与在这些小鼠中观察到的视网膜功能下降和与年龄相关的视网膜变性一致。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下和视网膜内出血。这些发现清楚地表明 Cav-1 表达/功能对于维持强大的 BRB 至关重要，但这种调节的机制尚不清楚。第一个目标是利用细胞特异性、可诱导的基因缺失来确定 Cav-1 在调节视网膜色素上皮细胞屏障活性中的作用。第二个目标将测试 Cav-1 在上皮细胞-细胞接触和顶端过程中脂质和蛋白质的结构组织中的作用。最终目标将集中于 Na/K-ATP 酶失调的作用以及 Cav-1 如何调节 ATP 酶活性。公共卫生相关性：血视网膜屏障完整性丧失是导致失明的三种主要原因的常见病理：糖尿病性视网膜病变；年龄相关性黄斑变性；和早产儿视网膜病变。该项目旨在研究调节血视网膜屏障完整性的机制，以确定改善病理性血视网膜屏障渗透性的新的潜在治疗策略。