GPR119: A novel means to lower intraocular pressure?

GPR119：降低眼压的新方法？

• 批准号: 8309048
• 负责人: ALEXANDER J STRAIKER
• 金额: $ 19.25万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309048
• 关键词: Adrenergic Agents; Agonist; Anterior; Aqueous Humor; Blindness; Cannabinoids; Ciliary Body; Circadian Rhythms; Clinical; Contralateral; Eye; Frozen Sections; G-Protein-Coupled Receptors; Glaucoma; Iris; Knock-out; Ligands; Measurement; Mediating; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pattern; Phase; Physiologic Intraocular Pressure; Prostaglandins; Regulation; Relative (related person); Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Specificity; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Trabecular meshwork structure; Vision; adrenergic; base; immunocytochemistry; insulin secretion; interest; knockout animal; mRNA Expression; mouse model; novel; novel strategies; novel therapeutics; oleoylethanolamide; palmidrol; receptor; research study; trend

GPR119 is a G protein-coupled receptor whose stimulation increases insulin secretion. GPR119 agonists are currently in phase II clinical trails as novel therapeutics for treating type II diabetes. However, the role of GPR119 has not been examined in the eye. In preliminary studies we have found that GPR119 and candidate endogenous ligands oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are all present in the anterior eye of the mouse. Notably, GPR119 is expressed prominently in the trabecular meshwork, responsible for outflow of aqueous humor. Preliminary functional experiments show that OEA reduces intraocular pressure (IOP) by 30% in the mouse. Elevated IOP is associated with most forms of glaucoma, a major cause of blindness worldwide. Our results suggest that a GPR119-based signaling system is present in the anterior eye and that GPR119 regulates intraocular pressure. The proposal will test this hypothesis as three specific aims. 1) Where are GPR119 receptors expressed in the murine eye? We will determine the expression pattern of GPR119 using immunocytochemistry in frozen sections of mouse eye, with GPR119 knockout controls. We will separately evaluate GPR119 mRNA expression using RT-PCR. 2) Are the putative endogenous GPR119 ligands present in the murine anterior eye? Using LC-MS we will determine the levels and diurnal variation of PEA and OEA in the anterior eye of the mouse. 3) Does GPR119 activation reduce intraocular pressure in a mouse model? Using the Tonolab measurement system we will extend preliminary experiments by testing OEA, PEA, and the potent synthetic agonist AR231453, with GPR119 knockout animals as controls. We will also test the interaction of GPR119-mediated reduction of IOP with beta-adrenergic-, alpha-adrenergic- and prostaglandin-based IOP- lowering treatments. Preliminary results suggest that GPR119 may be an entirely new means of reducing IOP, with considerable implications for glaucoma and therefore of great therapeutic potential.

GPR119是一种G蛋白偶联受体，其刺激可增加胰岛素的分泌。 GPR119激动剂目前处于II期临床试验，作为治疗 治疗II型糖尿病。然而，GPR119的作用还没有在 眼睛。在初步研究中，我们发现GPR119和候选基因内源性 配体油酰乙醇胺(OEA)和棕榈酰乙醇胺(PEA)都存在于 老鼠的前眼。值得注意的是，GPR119在 小梁网，负责房水流出。初步功能 实验表明，OEA可使小鼠的眼压降低30%。 高眼压与大多数形式的青光眼有关，青光眼是导致失明的主要原因 全世界。我们的结果表明，一个基于GPR119的信令系统存在于 GPR119调节眼压。这项提案将检验这一点 假设为三个具体目标。 1)GPR119受体在小鼠眼睛的哪里表达？我们将决定 冰冻切片中GPR119表达的免疫细胞化学研究 鼠标眼，带有GPR119击倒控制。我们将单独评估GPR119 逆转录-聚合酶链式反应检测mRNA的表达。 2)推测的内源性GPR119配体存在于小鼠的前额叶 眼睛?利用LC-MS测定PEA和PEA的水平和日变化 OEA在小鼠的前眼。 3)在小鼠模型中，GPR119的激活是否降低了眼压？vbl.使用 我们将通过测试Tonolab测量系统来扩展初步实验 OEA、PEA和具有GPR119基因敲除的有效合成激动剂AR231453 动物作为对照。我们还将测试GPR119介导的减数的相互作用 以β-肾上腺素、α-肾上腺素和前列腺素为基础的眼压 降低治疗水平。 初步结果表明，GPR119可能是一种全新的降低 眼压对青光眼有相当大的影响，因此具有很好的治疗作用 潜力。