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Cannabinoid Receptors and Novel Antiglaucoma Drugs

大麻素受体和新型抗青光眼药物

基本信息

批准号：
7895529
负责人：
ZHAO-HUI SONG
金额：
$ 37万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2012-07-31
项目状态：
已结题

项目摘要

Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shown that marijuana and its active components cannabinoids lower IOP. This project is focused on understanding the mechanisms by which cannabinoids, potential therapeutic agents for glaucoma, lower intraocular pressure (IOP). In the previous funding period, we have established that CB1 and CB2 cannabinoid receptors are expressed on the trabecular meshwork (TM) cells, and cannabinoid agonists enhance aqueous humor outflow through both CB1 and CB2 receptors. For the competitive renewal application of this project, we hypothesize that non-CB1/CB2 cannabinoid derivatives may cause an enhancement of aqueous humor outflow through a novel, non-CB1/CB2 cannabinoid receptor, and the novel cannabinoid receptor may mediates the IOP-lowering effects of the non-CB1/CB2 cannabinoid agonists through metalloprotease (MMP)-mediated mechanisms. Two specific aims are designed to test the above three hypotheses. Specific Aim 1: To study the effects of non-CB1/CB2 cannabinoid agonists, and the role of GPR55, a novel, non- CB1/CB2 cannabinoid receptor on aqueous humor outflow. Specific Aim 2: To study the mechanisms of actions for the aqueous humor outflow-enhancing effects of non-CB1/CB2 cannabinoid agonists. Completing this project should provide mechanistic insight regarding cannabinoid-induced enhancement of aqueous humor outflow facility. These studies should also contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development of better therapeutic agents for lowering IOP.

青光眼是世界范围内导致失明的主要原因之一。眼内压（IOP）升高是主要风险青光眼视神经损伤的因素。对人类受试者和动物模型进行的许多研究表明，大麻及其活性成分大麻素能降低眼压。该项目的重点是了解大麻素是青光眼的潜在治疗剂，它降低眼内压（IOP）的机制。在在上一个资助期，我们已经确定CB 1和CB 2大麻素受体在小梁上表达，网状（TM）细胞，和大麻素激动剂通过CB 1和CB 2受体增强房水流出。对于该项目的竞争性更新应用，我们假设非CB 1/CB 2大麻素衍生物可能通过一种新的非CB 1/CB 2大麻素受体引起眼房水流出的增强，大麻素受体可能通过以下途径介导非CB 1/CB 2大麻素激动剂的IOP降低作用：金属蛋白酶（MMP）介导的机制。本文设计了两个具体目标来检验上述三个假设。具体目的1：研究非CB 1/CB 2大麻素激动剂的作用，以及GPR 55的作用，GPR 55是一种新的非CB 1/CB 2大麻素激动剂。 CB 1/CB 2大麻素受体对房水流出的影响具体目标2：研究非CB 1/CB 2大麻素激动剂的房水流出增强作用。完成该项目应提供关于大麻素诱导的房水流出功能增强的机制见解。这些研究应也有助于我们理解房水流出的内稳态，并可能导致更好的降眼压治疗药物。