The Role of Outer Retinal Injury in Glaucoma

尽管治疗取得了进展，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，传统上认为视神经损伤是通过对视网膜神经节细胞（RGC）轴突的机械损伤或通过减少流向神经的血流而发生的。 然而，主要研究者及其同事最近报告了诊断为青光眼的人类和慢性青光眼实验模型中锥体光感受器损伤的形态学证据。 该小组还发现了分子水平损伤的证据。 具体而言，在实验性青光眼以及人青光眼中，L/M-视锥细胞（长波长和中波长敏感性）中视蛋白特异性信使RNA的产生减少。 初步的电生理数据还表明视锥细胞的部分功能受损，这似乎在已知在人类慢性青光眼中最早受到影响的弓形（中周边）区域中最为突出。 基于这些发现，提出了另一种假设，可能有助于青光眼RGC死亡的机制。 也就是说，升高的IOP导致脉络膜血流减少，从而引起对光感受器的缺血性损伤。 随后是损害作用（可能涉及由于再摄取或转运减少而导致的谷氨酸水平升高）沿顺行方向传递到视网膜内层，导致或加剧RGC损伤。 本建议的目的是测试这一顺行性假说的具体预测有关的脉络膜血流的变化和功能的事件发生在实验性青光眼模型的序列。 实验包括：使用微球撞击技术测量脉络膜血流量，用视蛋白特异性探针进行原位杂交和mRNA酶保护测定，以及多焦点和全场视网膜电图。

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.