EXCITATORY AMINO ACIDS IN GLAUCOMA

青光眼中的兴奋性氨基酸

• 批准号: 2518759
• 负责人: EVAN B. DREYER
• 金额: $ 14.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518759
• 关键词: Primates; calcium indicator; cellular pathology; clinical research; digital imaging; glaucoma; glutamates; human subject; inhibitor /antagonist; laboratory rat; retinal ganglion; tissue /cell culture; voltage /patch clamp

DESCRIPTION: Most therapy for glaucoma is directed at the management of the intraocular pressure (IOP). Conventional wisdom holds that excessive pressure within the eye leads to the ganglion cell loss/optic nerve damage seen in this disease. The data presented in this application, however, suggest that toxic levels of glutamate can contribute to glaucomatous visual loss. Both glutamate and elevated IOP can selectively damage the retinal ganglion cells of the optic nerve. The PI has identified an 2-3 fold elevation of glutamate in the vitreous of glaucoma patients. In the monkey model of laser-induced glaucoma, the elevation is even higher (to 5-7 times the control values). The PI has established that a 2-3 fold elevation of glutamate in the rat vitreous--when sustained for an extended period of time--can lead to the loss of retinal ganglion cells in a pattern that is very similar to that seen in human glaucoma. Therefore, even if the elevation of glutamate he has observed is simply a byproduct of the neuronal damage-- the concentration of glutamate he has found in glaucomatous vitreous is sufficient on its own to cause ganglion cell loss. In this grant proposal, he will investigate the following hypotheses: (1) The central hypothesis is that glutamate is elevated in the vitreous of glaucoma patients. Analysis of additional primate (human and monkey) samples may help in identifying whether the glaucoma diagnosis, or anti-glaucoma therapy plays a role in glutamate elevation. (2) He hypothesizes that the excess glutamate arises from the retina, either from ganglion or Muller cells. (3) If glutamate toxicity plays a role in glaucomatous loss, then drugs that can block glutamate damage may be effective in controlling glaucomatous blindness. (3A) He will first evaluate glutamate antagonists in a model of chronic glutamate toxicity. (3B) If these drugs are successful at blocking chronic glutamate toxicity, then (if glutamate toxicity is important in glaucoma) these agents should also retard glaucomatous loss. The PI will therefore test these drugs in a rat glaucoma model. These experiments will help test the central hypothesis--for if one can block the effects of IOP elevation with glutamate antagonists, then elevated IOP may toxic glutamate levels ganglion cell loss.

描述：大多数青光眼治疗都是针对青光眼的治疗 眼压（IOP）。 传统观点认为，过度 眼内压力导致神经节细胞丢失/视神经损伤 见于本病。 然而，本申请中提供的数据 表明有毒水平的谷氨酸可导致青光眼性视力 损失。 谷氨酸和升高的眼压都会选择性地损害视网膜 视神经的神经节细胞。 PI 已确定 2-3 倍 青光眼患者玻璃体内谷氨酸含量升高。 在猴子身上 激光诱发青光眼模型，海拔更高（达到5-7倍） 控制值）。 PI 已确定 2-3 倍的提升 大鼠玻璃体中的谷氨酸盐——当持续较长时间时 时间——会导致视网膜神经节细胞的损失，其模式是 与人类青光眼非常相似。 因此，即使 他观察到谷氨酸的升高只是神经元的副产品 损害——他在青光眼患者中发现的谷氨酸浓度 玻璃体本身就足以引起神经节细胞损失。 在这项拨款提案中，他将研究以下假设： (1) 中心假设是玻璃体中谷氨酸含量升高 青光眼患者。 其他灵长类动物（人类和猴子）的分析 样本可能有助于确定青光眼诊断或 抗青光眼治疗在谷氨酸升高中发挥作用。 (2) 他假设过量的谷氨酸来自视网膜，或者 来自神经节细胞或穆勒细胞。 (3) 如果谷氨酸毒性在青光眼消失中起作用，那么药物 可以阻止谷氨酸损伤可能有效控制青光眼 失明。 (3A) 他将首先在模型中评估谷氨酸拮抗剂 慢性谷氨酸中毒。 (3B) 如果这些药物能够成功阻断 慢性谷氨酸毒性，那么（如果谷氨酸毒性在 青光眼）这些药物还可以延缓青光眼的消失。 PI 将 因此，在大鼠青光眼模型中测试这些药物。 这些实验将 帮助检验中心假设——是否可以阻止眼压的影响 谷氨酸拮抗剂导致眼压升高，然后眼压升高可能会导致谷氨酸中毒 水平神经节细胞损失。