EXCITATORY AMINO ACIDS IN GLAUCOMA

青光眼中的兴奋性氨基酸

• 批准号: 6384359
• 负责人: ALAN M LATIES
• 金额: $ 26.81万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384359
• 关键词: Muller's cell; NMDA receptors; Primates; calcium indicator; cellular pathology; digital imaging; excitatory aminoacid; glaucoma; glutamate receptor; glutamate transporter; glutamates; human tissue; immunocytochemistry; in situ hybridization; inhibitor /antagonist; laboratory rat; neuroprotectants; northern blottings; retinal ganglion; tissue /cell culture

DESCRIPTION: Most therapy for glaucoma is directed at the management of the intraocular pressure (10P). 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 10P 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 10P may toxic glutamate levels ganglion cell loss.

描述：大多数青光眼疗法针对眼内压（10p）的管理。传统的智慧认为，眼睛内的压力过大会导致这种疾病中的神经节细胞丧失/视神经损伤。但是，本应用程序中提供的数据表明，谷氨酸的毒性水平可以导致青光眼视觉丧失。谷氨酸和升高的10p均可有选择地损害视神经的视网膜神经节细胞。 PI在青光眼患者的玻璃体中确定了谷氨酸的2-3倍升高。在激光诱导的青光眼的猴子模型中，高程甚至更高（是控制值的5-7倍）。 PI已经确定，在大鼠玻璃体中谷氨酸的2-3倍升高（当时长期持续时）会导致视网膜神经节细胞的丧失，这种模式与在人青光眼中所见的模式非常相似。因此，即使他观察到的谷氨酸升高只是神经元损伤的副产品 - 他在青光眼玻璃体中发现的谷氨酸浓度本身就足够了，可以引起神经节细胞的丧失。在该赠款提案中，他将研究以下假设：（1）中心假设是青光眼患者的玻璃体中谷氨酸升高。对其他灵长类动物（人类和猴子）样品的分析可能有助于确定青光眼诊断或抗云可瘤治疗是否在谷氨酸升高中起作用。 （2）他假设多余的谷氨酸来自视网膜，无论是神经节或穆勒细胞。 （3）如果谷氨酸毒性在青光眼损失中起作用，那么可以阻断谷氨酸损伤的药物可能有效控制青光眼失明。 （3A）他将首先在慢性谷氨酸毒性模型中评估谷氨酸拮抗剂。 （3B）如果这些药物成功地阻断了慢性谷氨酸毒性，那么（如果在青光眼中谷氨酸毒性很重要），这些药物也应延迟青光眼损失。因此，PI将在大鼠青光眼模型中测试这些药物。这些实验将有助于检验中央假设 - 如果可以阻止谷氨酸拮抗剂IOP升高的影响，则升高10p的10p五月有毒谷氨酸含量神经节细胞损失。