Harnessing endogenous cannabinoids for ocular health

描述（由申请人提供）：青光眼是两种最常见的失明形式之一，全世界有数百万例。眼压升高是青光眼的主要危险因素，大多数青光眼药物都是针对降低眼压的。虽然这些药物有多种种类，但每种都有局限性，并不是所有患者都对它们有反应。此外，由于青光眼治疗需要数年甚至数十年的时间，许多患者产生了耐药性，而没有治疗选择。在这种情况下，重要的是要注意大麻素已被发现对标准治疗有抗药性的患者有效。1971年，Hepler & Frank首次发表论文，证明大麻的主要精神活性成分THC对眼压（IOP）有有益作用。这引发了40年的一系列研究，以了解这种效应的本质，这些研究一直持续到今天。由于生理靶点未知，最初的工作集中在四氢大麻酚和相关的植物大麻素上。随着大麻素CB1和CB2受体以及内源性大麻素，2-AG和anandamide的鉴定，这些受体和配体成为大多数后续研究的目标。目前的建议代表了这些问题的下一个逻辑延伸：1)确定眼内源性大麻素系统的结构——代谢内源性大麻素（eCBs）的酶和产生它们的酶。初步结果表明，大麻素信号系统中的大多数“参与者”都存在于前眼。2)我们建议通过增强内源性信号传导来降低IOP。我们有证据表明，阻断MAGL（与代谢2-AG最相关的酶）可降低IOP，有趣的是，COX阻断剂对乙酰氨基酚可通过CB1降低IOP。重要的是，由于大麻素与神经保护密切相关，我们打算利用几种眼部病理模型来利用内源性大麻素来保护神经元。这一点很重要，因为IOP升高并不是青光眼的唯一危险因素，大麻素不仅可以降低IOP，还可以保护神经元免受青光眼相关损伤。令人惊讶的是，尽管大麻素具有降低IOP和作为神经保护剂的潜力，但我们对CB1表达以外的眼大麻素知之甚少。青光眼仍然是一种影响数百万人的毁灭性疾病；提出的研究有可能极大地扩展我们对眼大麻素信号的认识，并确定与眼健康相关的新型药物。

DESCRIPTION (provided by applicant): Glaucoma is one of the two most common forms of blindness, causing millions of cases worldwide. Elevated intraocular pressure (IOP) is the main risk factor and most glaucoma drugs are directed at lowering ocular pressure. While multiple classes of these drugs are available each has limitations and not all patients respond to them. Moreover because glaucoma treatments are required for years or even decades many patients develop tolerance and are left without treatment options. In this context it is important to note that cannabinoids have been found to be effective in patients resistant to standard therapies. 1971 marked the publication of the first work by Hepler & Frank demonstrating that the chief psychoactive ingredient of marijuana - THC - has a salutary effect on intraocular pressure (IOP). This set in motion a 40-year series of studies to learn the nature of this effect, studies that continue today. Because the physiological target was unknown, initial work focused on THC and related phytocannabinoids. With the identification of the cannabinoid CB1 and CB2 receptors and endocannabinoids, 2-AG and anandamide, these receptors and ligands became the target of most subsequent studies. The current proposal represents the next logical extension of these inquiries: 1) to determine the architecture of the ocular endocannabinoid system -- the enzymes that metabolize the endogenous cannabinoids (eCBs) and the enzymes that produce them. Preliminary results show that most 'players' in the cannabinoid signaling system are present in the anterior eye. 2) We propose to enhance endogenous signaling to reduce IOP. We have evidence that blocking MAGL the enzyme most implicated in metabolizing 2-AG lowers IOP and intriguingly that the COX blocker acetaminophen lowers IOP via CB1. Importantly since cannabinoids are strongly implicated in neuroprotection we intend to 3) harness endocannabinoids to protect neurons using several models of ocular pathology. This is important because elevated IOP is not the only risk factor for glaucoma and raises the possibility that cannabinoids may be engaged not only to reduce IOP but also to protect neurons from damage associated with glaucoma. We know surprisingly little about ocular cannabinoids beyond CB1 expression despite the proven potential of cannabinoids to lower IOP and to serve as neuroprotective agents. Glaucoma remains a devastating disease that affects millions; the proposed research has the potential to greatly expand our knowledge of ocular cannabinoid signaling and to identify novel classes of drugs related to ocular health.