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: 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
• 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

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（由申请人提供）：血液视网膜屏障（BRB）有选择地调节神经视网膜的局部环境。 BRB完整性的丧失是失明的三个主要原因的常见病理：糖尿病性视网膜病；与年龄相关的黄斑变性；和早产的视网膜病变。最近的证据表明，Caveolin-1（Cav-1）是一种称为Caveolae的专门脂质微域的积分蛋白成分，对于正常的视网膜功能至关重要。 CAV-1 NULL小鼠在CAV-1 NULL小鼠中表现出降低的视网膜功能，如受感受器缺陷所示的电图（ERG）所示。但是，这种降低的光感受器功能无法通过对光转导的直接影响来解释，因为在分离的Cav-1 null杆的记录中响应正常。这表明Cav-1 Null视网膜中的功能不足是由光感受器周围异常的局部环境引起的。为了支持这一假设，令人信服的证据表明Cav-1 null小鼠具有超可渗透的BRB。渗透率增加与紧密连接，Na/k-ATPase活性的变化和视网膜外水肿的改变相关。 CAV-1 NULL小鼠提供了令人信服的数据，显示了视网膜色素上皮和血管屏障功能的明显丧失。这种提高的渗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降低和与年龄相关的视网膜变性一致。此外，当经受应力范式（氧诱导的视网膜病）时，CAV-1 null小鼠显示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，但是该调节的机制尚不清楚。第一个目的旨在确定CAV-1在使用细胞特异性的，可诱导的遗传缺失的视网膜色素上皮中专门调节屏障活性中的作用。第二个目的将测试CAV-1在脂质和蛋白质的结构组织中的作用，在上皮细胞 - 细胞接触和根尖过程中。最终目标将集中于Na/k-ATPase发挥作用以及CAV-1如何调节ATPase活性的作用。 公共卫生相关性：丢失归归性屏障完整性是三种主要原因的常见病理：糖尿病性视网膜病变；与年龄有关的黄斑变性；和早产的视网膜病变。该项目旨在研究调节血红视网膜屏障完整性的机制，以定义新型的潜在治疗策略，以减轻病理血液视网膜屏障的渗透性。