The RPE and Recovery of the Blood Retina Barrier

摘要： 视网膜色素上皮(RPE)是外部神经视网膜和脉络膜之间的主要屏障， 形成血视网膜屏障(BRB)的一部分。对RPE细胞和RPE组织的损害 黄斑变性、葡萄膜炎、视网膜变性和视网膜脱离都会损害黄斑裂孔。另外， 视网膜下手术或视网膜下注射可能会对RPE造成损害。他人的大量工作 非眼上皮单分子层表明这些组织对压力做出反应并恢复其结构 并通过少量的保护机制发挥作用。我们初步的实验观察 建议RPE对损伤或疾病做出类似的反应，通过可定义的保护来恢复BRB 机械装置。从这些观察中，我们假设：a)有有限数量的回复 RPE需要恢复BRB；b)每种反应导致RPE细胞死亡的独特模式；c)每种反应 响应类型不同，因此建模BRB修复必须灵活(图1)。 出于这些原因，我们建议在这里测试RPE用来响应侮辱和 恢复慢性轻、中、重度损伤后的BRB。而屏障功能的恢复 已经在果蝇的翅膀、肺泡中进行了研究，而在整个胚胎学中，它还没有在 RPE表。大多数关于上皮单层的研究，无论是在RPE中还是在非眼组织中，都使用2- 三维(2D)静态或延时运动显微技术，用于研究损伤响应。在这个项目中，我们 采用来自外部视觉研究的智能软件和数学工具，使用定量时空 (4D：空间3D和时间1D)动力学，以探索单个RPE细胞和 RPE表。 意义：完成这些目标将增加我们对时空动力学和 RPE细胞在短期或长期、低至高水平毒性侮辱后修复BRB的生物力学研究。这 对致盲机制的新认识将使我们能够纠正致盲过程中基本屏障功能的丧失 通过启动早期和廉价的干预措施来预防和控制疾病。

Summary: The retinal pigment epithelium (RPE) is the major barrier between the outer neural retina and the choroid, forming part of the blood retina barrier (BRB). Damage to the RPE cell and to the organization of the RPE sheet impairs the BRB, as seen in AMD, uveitis, retinal degenerations, and retinal detachment. Additionally, damage to the RPE can occur following subretinal surgery or subretinal injections. Extensive work by others with non-ocular epithelial monolayers indicates that such tissues respond to stress and restore their structure and function through a small number of protective mechanisms. Our preliminary experimental observations suggest that the RPE similarly responds to damage or disease, restoring the BRB via definable protective mechanisms. From these observations, we hypothesize: a) There are a limited number of responses that the RPE takes to restore the BRB; b) Each kind of response results in a unique pattern of RPE cell death; c) Each response type differs, thus modeling BRB repair must be flexible (Fig 1). For these reasons, we propose here to test for specific mechanisms that the RPE uses to respond to insult and to restore the BRB following chronic mild, moderate, and severe injury. While restoration of barrier functions has been investigated in Drosophila wings, lung alveoli, and throughout embryology, it has not been studied in the RPE sheet. Most research on epithelial monolayers, whether in RPE or in non-ocular tissue, uses 2- dimensional (2D) static or time-lapse motion photomicroscopy to study damage responses. In this project, we adapt clever software and mathematical tools from outside vision research that use quantitative spatiotemporal (4D: 3D in space & 1D in Time) dynamics to explore the damage responses of individual RPE cells and of the RPE sheet. Significance: Completion of these Aims will increase our understanding of spatiotemporal dynamics and biomechanics of repair of the BRB after short- or long-term, low- to high-level toxic insults to RPE cells. This new understanding of mechanisms will allow us to correct the loss of essential barrier function in blinding diseases by initiating early and inexpensive interventions.