Harnessing endogenous cannabinoids for ocular health

利用内源性大麻素促进眼部健康

• 批准号: 9334870
• 负责人: ALEXANDER J STRAIKER
• 金额: $ 31.77万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334870
• 关键词: 2-arachidonylglycerol; ABHD12 gene; ABHD6 gene; Acetaminophen; Affect; Animals; Anterior; Architecture; Axotomy; Blindness; CNR1 gene; CNR2 gene; Cannabinoids; Disease; Drug Kinetics; Endocannabinoids; Enzymes; Experimental Models; Eye; Glaucoma; Health; In Vitro; Knock-out; Knowledge; Learning; Left; Ligands; Marijuana; Metabolic; Metabolism; Microspheres; Modeling; Motion; Mus; NAAA gene; Nature; Nerve Degeneration; Neurons; Neuroprotective Agents; Ocular Pathology; Optic Nerve; Optic Nerve Injuries; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Physiological; Positioning Attribute; Property; Proteins; Publications; Publishing; Regulation; Reperfusion Therapy; Research; Resistance; Retina; Retinal; Risk Factors; Series; Signal Transduction; System; Testing; Therapeutic; Work; anandamide; anterior chamber; cannabinoid receptor interacting protein 1a; desensitization; endogenous cannabinoid system; ganglion cell; in vivo Model; knockout animal; mRNA Expression; neuroprotection; normotensive; novel; novel drug class; optic nerve disorder; phytocannabinoid; pressure; prevent; protein expression; public health relevance; receptor; retinal ischemia; tool

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.

描述（由申请人提供）：青光眼是两种最常见的失明形式之一，在全球范围内造成数百万例病例。眼内压（IOP）升高是主要的危险因素，大多数青光眼药物都是针对降低眼压。虽然有多种类型的这些药物可供使用，但每种药物都有局限性，并非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，许多患者产生耐受性并且没有治疗选择。在这种情况下，重要的是要注意，大麻素已被发现对标准疗法有抵抗力的患者有效。1971年，Hepler & Frank发表了第一篇论文，证明大麻的主要精神活性成分- THC -对眼内压（IOP）有有益的影响。这引发了一系列长达40年的研究，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THC和相关的植物大麻素。随着大麻素CB 1和CB 2受体以及内源性大麻素、2-AG和大麻素的鉴定，这些受体和配体成为大多数后续研究的目标。目前的提议代表了这些调查的下一个逻辑延伸：1）确定眼部内源性大麻素系统的结构-代谢内源性大麻素（eCB）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”都存在于前眼中。2)我们建议增强内源性信号传导以降低IOP。我们有证据表明，阻断MAGL（与2-AG代谢最相关的酶）可降低IOP，有趣的是，考克斯阻断剂对乙酰氨基酚通过CB 1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3）利用内源性大麻素来保护神经元，使用几种眼部病理模型。这一点很重要，因为IOP升高并不是青光眼的唯一风险因素，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，我们对CB 1表达以外的眼部大麻素知之甚少，尽管大麻素被证明有降低IOP和作为神经保护剂的潜力。青光眼仍然是一种影响数百万人的毁灭性疾病;拟议的研究有可能极大地扩展我们对眼部大麻素信号传导的了解，并确定与眼部健康相关的新型药物。

项目成果

Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.

• DOI: 10.1167/iovs.16-19356
• 发表时间: 2016-06-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Miller S;Leishman E;Hu SS;Elghouche A;Daily L;Murataeva N;Bradshaw H;Straiker A
• 通讯作者: Straiker A

Revisiting cannabinoid receptor 2 expression and function in murine retina.

• DOI: 10.1016/j.neuropharm.2018.08.007
• 发表时间: 2018-10
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Borowska-Fielding J;Murataeva N;Smith B;Szczesniak AM;Leishman E;Daily L;Toguri JT;Hillard CJ;Romero J;Bradshaw H;Kelly MEM;Straiker A
• 通讯作者: Straiker A

Cannabinoid receptor-mediated modulation of inhibitory inputs to mitral cells in the main olfactory bulb.

大麻素受体介导的对主嗅球二尖瓣细胞的抑制性输入的调节。

• DOI: 10.1152/jn.00100.2018
• 发表时间: 2019
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Wang,Ze-Jun;Hu,SherryShu-Jung;Bradshaw,HeatherB;Sun,Liqin;Mackie,Ken;Straiker,Alex;Heinbockel,Thomas
• 通讯作者: Heinbockel,Thomas

Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.

• DOI: 10.1167/iovs.16-19437
• 发表时间: 2016-11-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Miller S;Leishman E;Oehler O;Daily L;Murataeva N;Wager-Miller J;Bradshaw H;Straiker A
• 通讯作者: Straiker A