Role of advanced glycation end products (AGEs) in primary open angle glaucoma - PROJECT SUMMARY Glaucoma is the second leading cause of blindness, characterized by progressive damage to the optic nerve. About 80 million people are globally affected by this disease, and nearly 11 million are blind from it. Primary open-angle glaucoma (POAG) is the most common type and accounts for up to 80% of all glaucoma cases. It is characterized by an open, normal-appearing anterior chamber angle and elevated intraocular pressure (IOP) with no specific ocular abnormalities. The elevation of IOP, a significant and only modifiable risk factor in POAG, is due to the greater resistance of the drainage system. About 80–90% of aqueous humor exits the eye via the trabecular meshwork (TM). TM cells synthesize and secrete extracellular matrix (ECM) proteins, which have negligible turnover and accumulate chemical modifications during aging. The overarching hypothesis of this proposal is that the accumulation of advanced glycation end products (AGEs) in TM promotes ECM protein synthesis by the TM cells and causes resistance to AH outflow in POAG. This hypothesis will be tested by the following two specific aims. In Aim 1, we will test the hypothesis that AGEs in the TM lead to ECM remodeling and TM cell dysfunction. To test this, we will compare AGE levels in TM tissues from POAG patients and controls, examine AGE-induced ECM and cellular changes, perform RNA sequencing to identify affected signaling pathways, and assess the therapeutic potential of an AGE receptor antagonist. In Aim 2, we will investigate whether increasing AGE levels in TM contributes to increased outflow resistance and IOP elevation, using a sustained-release system to deliver AGE precursors into mouse eyes. By targeting AGE receptor utilizing a receptor antagonist treatment or receptor-deficient mice, we will explore the therapeutic potential of targeting AGE-RAGE interaction to mitigate TM damage and reduce outflow resistance. The proposed project is expected to uncover a novel mechanism for aqueous outflow resistance, and the findings could lead to innovative therapies to reduce IOP in POAG.
