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G蛋白偶联受体，其刺激会增加胰岛素的分泌。 GPR119激动剂目前处于II期临床踪迹中，作为新的治疗方法 治疗II型糖尿病。但是，GPR119的作用尚未在 眼睛。在初步研究中，我们发现GPR119和候选内生 配体乙醇酰胺（OEA）和棕榈乙醇酰胺（PEA）都存在于 老鼠的前眼。值得注意的是，GPR119在 小梁网，负责水性幽默的流出。初步功能 实验表明，OEA在小鼠中将眼内压（IOP）降低了30％。 升高的IOP与大多数形式的青光眼有关，这是失明的主要原因 全世界。我们的结果表明，基于GPR119的信号系统存在于 前眼，该GPR119调节眼内压。该提案将测试 假设是三个特定目标。 1）鼠眼中的GPR119受体在哪里表达？我们将确定 使用免疫细胞化学的GPR119的表达模式 鼠标，具有GPR119敲除控件。我们将分别评估GPR119 使用RT-PCR的mRNA表达。 2）是鼠前鼠中存在的假定内源性GPR119配体 眼睛？使用LC-MS，我们将确定PEA和PEA的水平和昼夜变化 在小鼠的前眼中OEA。 3）GPR119激活是否会降低小鼠模型中的眼内压？使用 Tonolab测量系统我们将通过测试扩展初步实验 OEA，PEA和有效的合成激动剂AR231453，GPR119敲除 动物作为对照。我们还将测试GPR119介导的还原的相互作用 IOP与β-肾上腺素能，α-肾上腺素能和前列腺素的IOP- 降低治疗。 初步结果表明GPR119可能是减少的全新手段 IOP，对青光眼具有很大的影响，因此具有出色的治疗性 潜在的。