EXCITATORY AMINO ACIDS IN GLAUCOMA

青光眼中的兴奋性氨基酸

• 批准号: 2628988
• 负责人: EVAN B. DREYER
• 金额: $ 14.75万
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2628988
• 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管理。 眼内压（IOP）。 传统观点认为， 眼内压力导致神经节细胞损失/视神经损伤 在这种疾病中看到。 然而，本申请中提供的数据， 表明毒性水平的谷氨酸会导致昏迷性视觉障碍， 损失 谷氨酸盐和高眼压都可以选择性地损害视网膜 视神经的神经节细胞 PI已经确定了2-3倍 青光眼患者玻璃体中谷氨酸升高。 在猴中 激光诱导的青光眼模型，升高甚至更高（至5-7倍 控制值）。 PI已经确定， 谷氨酸在大鼠玻璃体-当持续一段时间的延长， 时间-可以导致视网膜神经节细胞的损失， 非常类似于在人类青光眼中看到的。 因此即使 他观察到的谷氨酸盐的升高仅仅是神经元 他在昏迷病人体内发现谷氨酸的浓度 玻璃体本身足以引起神经节细胞损失。 在本研究中，他将研究以下假设： (1)中心假设是谷氨酸在玻璃体中升高， 青光眼患者。 其他灵长类动物（人和猴）的分析 样本可能有助于确定是否患有青光眼诊断，或者 抗青光眼治疗在谷氨酸升高中起作用。 (2)他假设过量的谷氨酸来自视网膜， 神经节或米勒细胞的细胞。 (3)如果谷氨酸毒性在昏迷性脑损伤中起作用， 可以阻断谷氨酸损伤， 失明 (3A)他将首先评估谷氨酸拮抗剂在一个模型， 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），这些药物也应该延缓青光眼的损失。 PI将 因此在大鼠青光眼模型中测试这些药物。 这些实验将 帮助验证中心假设--如果一个人可以阻止IOP的影响， 谷氨酸拮抗剂升高，则IOP升高可能毒性谷氨酸 水平神经节细胞损失。