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个病例。眼内压力（IOP）是主要危险因素，大多数青光眼药物针对降低眼压。尽管有多种类药物可用，虽然每个药物都有局限性，但并非所有患者都会对其做出反应。此外，由于数年甚至几十年需要青光眼治疗，许多患者需要耐受性，并且没有治疗选择。在这种情况下，重要的是要注意，已经发现大麻素对耐标准疗法具有抗性患者有效。 1971年标志着Hepler＆Frank撰写的第一部作品的出版，证明了大麻的主要精神活性成分-THC-对眼内压力（IOP）具有有益的影响。这使这项研究启动了40年的研究，以了解这种效果的性质，这是今天继续进行的研究。由于生理靶标未知，因此初始工作集中在THC和相关的植物大麻素上。通过鉴定大麻素CB1和CB2受体以及内源性大麻素，2-AG和Anandamide，这些受体和配体成为了最后续研究的目标。当前的提案代表了这些查询的下一个逻辑扩展：1）确定眼内表大麻素系统的结构 - 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“玩家”都存在于前眼中。 2）我们建议增强内源信号传导以减少IOP。我们有证据表明，阻断含量最大的酶与代谢2-ag降低了IOP，并有趣地表明，Cox Blocker乙酰氨基酚通过CB1降低了IOP。重要的是，由于大麻素在神经保护作用上很大，因此我们打算使用多种眼科病理模型来保护神经元。这很重要，因为升高的IOP并不是青光眼的唯一危险因素，并且提高了大麻素可能不仅可以减少IOP，还可以保护神经元免受与青光眼相关的损害的可能性。尽管大麻素有可能降低IOP并充当神经保护剂，但我们对CB1表达以外的眼大麻素的了解却很少。青光眼仍然是一种毁灭性疾病，影响数百万。拟议的研究有可能大大扩展我们对眼部大麻素信号传导的了解，并确定与眼健康有关的新型药物。

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