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

项目总结 血-视网膜屏障(BRB)选择性地、紧密地调节神经视网膜的局部环境。 BRB完整性的丧失是导致失明的三个主要原因的常见病理：糖尿病视网膜病变；年龄- 相关性黄斑变性；早产儿视网膜病变。最近的证据表明，小窝蛋白-1(Cav-1) 1)，是专门的脂类微域的一个不可或缺的蛋白质成分，称为小窝，对于正常 视网膜功能。CAV-1基因缺失的小鼠表现出视网膜功能降低，如 视网膜电信号(ERG)显示是光感受器缺陷。然而，这减少了光感受器 功能不能用对光转导的直接影响来解释，因为在记录中反应是正常的 从孤立的CAV-1零棒。这表明Cav-1缺失视网膜的功能缺陷是由于 感光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基因缺失的小鼠具有高通透性的BRB。通透性的增加与 紧密连接改变，Na/K-ATPase活性改变，视网膜外部水肿。CAV-1基因缺失小鼠 提供令人信服的数据，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光感受器环境，这与视网膜减少是一致的 在这些小鼠中观察到与功能和年龄相关的视网膜退化。此外，当受到压力时， 范型(氧源性视网膜病变)，Cav-1基因缺失的小鼠表现出严重的视网膜下和视网膜内 大出血。这些发现清楚地表明Cav-1的表达/功能在维持中是必不可少的 但这一规定的机制(S)尚不清楚。第一个目标是确定 Cav-1在调节视网膜色素上皮细胞特异性屏障活性中的作用 可诱导的基因缺失。第二个目标将测试Cav-1在脂类结构组织和 上皮细胞-细胞接触和顶突中的蛋白质。最终目标将集中在监管失调所扮演的角色 Na/K-ATPase的作用以及Cav-1如何调节ATPase活性。

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.