Cannabinoid Receptors and Novel Antiglaucoma Drugs

大麻素受体和新型抗青光眼药物

• 批准号: 6681560
• 负责人: ZHAO-HUI SONG
• 金额: $ 29.22万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681560
• 关键词: binding sites; biological signal transduction; cannabinoid receptor; cannabinoids; cell biology; chemical binding; cytoskeleton; eye pharmacology; gene expression; glaucoma; human tissue; intraocular aqueous flow; intraocular pressure; metalloendopeptidases; molecular biology; ocular hypotensive; organ culture; perfusion; postmortem; protein localization; protein structure function; tissue /cell culture; trabecular meshwork; uvea ciliary body

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms for cannabinoids to lower intraocular pressure (IOP), and to provide a basis for developing novel cannabinoids with improved IOP-lowering properties, and devoid of psychoactive side-effects of marijuana. The central hypothesis to be tested in this proposal is that cannabinoids act on specific cannabinoid receptors in multiple targets of the outflow pathways to exert their IOP-lowering effects. To test this hypothesis, the following specific aims are planned. (1) To test the effects of cannabinoid ligands and the roles of cannabinoid receptors on outflow facility with perfused human ocular anterior segment, using recently developed high affinity and/or subtype-selective cannabinoid ligands. (2) To map the distribution of cannabinoid receptor subtypes in two potential targets of cannabinoids, trabecular meshwork and ciliary muscle. (3) To characterize ligand binding properties and signal transduction mechanisms of cannabinoid receptors in trabecular meshwork and ciliary muscle cells. (4) To determine the effects of cannabinoid ligands, the roles of cannabinoid receptors, and cannabinoid signaling pathways in regulating the cellular functions (such as cell cytoskeleton and matrix metalloproteases) of trabecular meshwork and ciliary muscle cells. A combination of molecular biology, cell biology and pharmacology approaches will be applied to the proposed research. Attempts will be made to correlate information gained from in vitro experiments with ex vivo organ perfusion studies in order to understand the roles of cannabinoid receptors and the mechanisms for the effects of cannabinoids on aqueous humor outflow. By investigating the mechanisms underlying the IOP-lowering effects of cannabinoids, this study may facilitate the discovery of more effective anti-glaucoma cannabinoid ligands. By deciphering specific ocular cannabinoid receptor subtypes that are involved in the IOP-lowering effects of cannabinoids, this study may help to separate the desired IOP-lowering effects of cannabinoids from their undesired psychoactive side-effects.

描述（由申请人提供）：该项目的长期目标是了解大麻素降低眼内压（IOP）的机制，并为开发具有改善的IOP降低特性的新型大麻素提供基础，并且没有大麻的精神副作用。在该提案中要测试的中心假设是大麻素作用于流出途径的多个靶点中的特定大麻素受体，以发挥其降低IOP的作用。为了检验这一假设，计划实现以下具体目标。(1)使用最近开发的高亲和力和/或亚型选择性大麻素配体，测试大麻素配体的作用和大麻素受体对灌注的人眼前节流出设施的作用。(2)绘制大麻素受体亚型在大麻素两个潜在靶点小梁网和睫状肌中的分布。(3)研究小梁网和睫状肌细胞中大麻素受体的配体结合特性和信号转导机制。(4)确定大麻素配体的作用，大麻素受体的作用，以及大麻素信号通路在调节小梁网和睫状肌细胞的细胞功能（如细胞骨架和基质金属蛋白酶）。将分子生物学、细胞生物学和药理学方法相结合，应用于拟议的研究。尝试将从体外实验中获得的信息与离体器官灌注研究相关联，以了解大麻素受体的作用和大麻素对房水流出的影响机制。通过研究大麻素降低IOP作用的机制，这项研究可能有助于发现更有效的抗青光眼大麻素配体。通过破译参与大麻素降低IOP作用的特定眼部大麻素受体亚型，这项研究可能有助于将大麻素的理想IOP降低作用与其不希望的精神副作用分开。