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.
Our preliminary results provide strong evidence for a GPR119-based signaling system in the mammalian eye, with receptors, ligands and function in the form of a 30% reduction in intraocular pressure. Elevated intraocular pressure is implicated in glaucoma, which causes impaired vision in millions of people around the world. The identification of a novel pathway to lower intraocular pressure is therefore of great therapeutic interest. !
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