Cannabinoid Receptors and Novel Antiglaucoma Drugs

青光眼是世界范围内导致失明的主要原因之一。眼压升高是主要的危险因素。 青光眼视神经损害的因素。许多针对人类受试者和动物模型的研究表明 大麻及其活性成分大麻素可降低眼压。本项目的重点是了解 大麻素是治疗青光眼的潜在药物，其降低眼压的机制。在 在之前的资助阶段，我们已经证实CB1和CB2大麻素受体在小梁上表达 Nethwork(TM)细胞和大麻素激动剂通过CB1和CB2受体增加房水流出。 对于这个项目的竞争性续签申请，我们假设非CB1/CB2大麻衍生物可能 通过一种新的、非CB1/CB2的大麻素受体引起房水流出增加，并且新的 大麻素受体可能通过以下途径介导非CB1/CB2类大麻激动剂的降眼压作用 金属蛋白酶(MMPs)介导的机制。我们设计了两个具体的目标来检验上述三个假设。 具体目的1：研究非CB1/CB2类大麻激动剂的作用，以及GPR55的作用。 房水流出时的CB1/CB2受体。具体目标2：研究针叶提取物的作用机制 非cb1/cb2类大麻激动剂的房水流出促进作用。完成这个项目应该会提供 关于大麻素诱导的房水流出设施增强的机制洞察。这些研究应该 也有助于我们理解房水流出的动态平衡，并可能导致 更好的降低眼压的治疗剂。

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.