IN VIVO ROLE OF CAVEOLIN-1 IN MODULATING PHOTORECEPTOR FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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、老年性黄斑变性和早产儿视网膜病变。最近的证据表明，小窝蛋白-1(Cav-1)对于正常的视网膜功能和BRB的完整性是必不可少的。CAV-1基因缺失的小鼠通过视网膜电描记术表现出视网膜功能下降，这不能用光感受器中CAV-1的丢失来解释。因此，Cav-1缺失视网膜的功能缺陷可能是由于光感受器周围的局部环境异常所致。为了支持这一假说，令人信服的证据表明，Cav-1基因缺失的小鼠表现出明显的RPE和血管屏障功能的丧失，这些功能与紧密连接的变化、Na/K-ATPase活性的变化和视网膜外部水肿有关。这个COBRE项目的目标是研究CAV-1调节RPE中BRB完整性的机制(S)。这些目标与2009年3月提交的R01申请一致。R01应用的第一个目的是确定Cav-1在通过细胞特异的、可诱导的基因缺失来调节RPE内的屏障活性方面的作用。第二个目标将测试Cav-1在上皮细胞-细胞接触和心尖过程中脂质和蛋白质的结构组织中的作用。最终目标将集中在Na/K-ATPase失调所起的作用以及Cav-1如何调节ATPase活性。

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. 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) is essential for normal retinal function and BRB integrity. Cav-1 null mice display reduced retinal function by electroretinography that cannot be explained by loss of Cav-1 specifically in photoreceptors. Thus, the functional deficit in Cav-1 null retinas likely results from an abnormal local environment surrounding photoreceptors. In support of this hypothesis, compelling evidence indicates that Cav-1 null mice display a clear loss of RPE and vascular barrier functions that correlate with alterations in tight junctions, changes in Na/K-ATPase activity, and outer retinal edema. 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 an R01 application submitted in March 2009. The first aim of the R01 application is designed to determine the role of Cav-1 in regulating barrier activity specifically within the RPE 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.