The Role of Outer Retinal Injury in Glaucoma

外视网膜损伤在青光眼中的作用

• 批准号: 6623130
• 负责人: T MICHAEL NORK
• 金额: $ 36.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623130
• 关键词: Macaca mulatta; RNase protection assay; apoptosis; electrodes; electroretinography; eye disorder diagnosis; eye injury; fluorescence microscopy; glaucoma; in situ hybridization; intraocular pressure; microcapsule; optic nerve; retina; retina circulation; retinal ganglion; rhodopsin; visual photoreceptor; visual phototransduction; visual stimulus

Despite advances in therapy, glaucoma remains one of the leading causes of blindness. In this disease, chronically elevated intraocular pressure (IOP) is a risk factor for optic nerve damage, which has traditionally been thought to occur either by mechanical damage to the retinal ganglion cell (RGC) axons, or by reduced blood flow to the nerve. However, the Principal Investigator and colleagues have recently reported morphologic evidence for injury to the cone photoreceptors in both humans with a diagnosis of glaucoma and in an experimental model of chronic glaucoma. This group has also found evidence for injury at the molecular level. Specifically, that there is decreased production of opsin-specific messenger RNA in the L/M- cones (long and medium wavelength-sensitive) in both experimental glaucoma as well as human glaucoma. Preliminary electrophysiological data also suggest partial functional impairment of the cones, which appears to be most prominent in the arcuate (mid-peripheral) region that is known to be affected earliest in human chronic glaucoma. Based on these findings, an alternative hypothesis is proposed for a mechanism that might contribute to RGC death in glaucoma. Namely, that elevated IOP results in decreased choroidal blood flow causing ischemic injury to the photoreceptors. This is followed by transmission of the damaging effects (perhaps involving elevated levels of glutamate due to decreased re-uptake or transport) in an anterograde direction to the inner retina, leading to or exacerbating RGC injury. The aim of this proposal is to test specific predictions of this anterograde hypothesis relating to alterations in choroidal blood flow and the functional sequence of events that occur in a model of experimental glaucoma. Experiments include: measurement of choroidal blood flow using a microsphere impaction technique, in situ hybridization and mRNAse protection assay with opsin specific probes, and multifocal as well as full-field electroretinography.

尽管在治疗方面取得了进步，但青光眼仍然是失明的主要原因之一。 在这种疾病中，长期升高的眼内压（IOP）是视神经损伤的危险因素，传统上认为这是通过机械损伤对视网膜神经节细胞（RGC）轴突的机械损伤而发生的，或者是通过降低神经流动的。 然而，主要研究者及其同事最近报告了伴有青光眼诊断和慢性青光眼实验模型的人群中锥形感受器损伤的形态学证据。 该组还发现了在分子水平上受伤的证据。 具体而言，在实验性青光眼和人青光眼中，在L/M锥（长和中等波长敏感）中，Opsin特异性信使RNA的产生降低。 初步的电生理数据还表明，锥体的部分功能障碍，在弓形（外膜中部）区域似乎最突出，该区域已知在人类慢性青光眼中受到最早的影响。 基于这些发现，提出了一种替代假设，用于可能导致青光眼中RGC死亡的机制。 也就是说，IOP升高会导致脉络膜血流降低，导致感光体缺血性损伤。 接下来是向内向视网膜的行进方向传播破坏性效应（可能涉及谷氨酸水平升高），导致或加剧了RGC损伤。 该提案的目的是测试与脉络膜血流改变以及实验性青光眼模型中发生的事件的功能序列有关的此类行为假设的特定预测。 实验包括：使用微球撞击技术测量脉络膜血流，原位杂交和用OPSIN特异性探针以及多灶和全场电视图测量。