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

• 批准号: 8197255
• 负责人: MICHAEL H ELLIOTT
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 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/8197255
• 关键词: ATP phosphohydrolase; Adhesions; Adhesiveness; Adult; Affect; Affinity; Age related macular degeneration; Apical; Bicarbonates; 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; Hemorrhage; 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 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; recombinase; response; retinal rods

Project summary 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 microdomains 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 hyperpermeable 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 subretinal and intraretinal 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.

项目概要 血视网膜屏障（BRB）选择性地、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) 是一种称为小凹的特殊脂质微结构域的完整蛋白质成分，对于正常细胞至关重要 视网膜功能。 Cav-1 缺失小鼠显示出 Cav-1 缺失小鼠的视网膜功能降低，如 视网膜电图（ERG）提示存在光感受器缺陷。然而，这种减少的光感受器 功能不能通过对光转导的直接影响来解释，因为记录中的反应是正常的 来自孤立的 Cav-1 零棒。这表明 Cav-1 无效视网膜的功能缺陷是由 光感受器周围的局部环境异常。为了支持这一假设，有令人信服的证据 表明 Cav-1 缺失小鼠具有高渗透性 BRB。增加的渗透性与 紧密连接的改变、Na/K-ATP酶活性的改变和外视网膜水肿。 Cav-1无效小鼠 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 通透性增加改变了正常的感光环境，这与视网膜减少一致 在这些小鼠中观察到功能和与年龄相关的视网膜变性。此外，当受到压力时 范例（氧诱导的视网膜病变），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 稳健的 BRB，但这种调节的机制尚不清楚。第一个目标旨在确定 Cav-1 在利用细胞特异性调节视网膜色素上皮内的屏障活性中的作用， 诱导性基因缺失。第二个目标是测试 Cav-1 在脂质结构组织中的作用， 上皮细胞-细胞接触和顶端过程中的蛋白质。最终目标将集中于失调的作用 Na/K-ATP 酶的作用以及 Cav-1 如何调节 ATP 酶活性。