Glaucoma is the second leading cause of blindness in the world after cataract, affecting approximately 70 million people. Elevated intraocular pressure due to the obstruction of the aqueous outflow pathway is a major causal risk factor in the development of primary open-angle glaucoma. Treatment of this blinding disease is compromised because of the lack of understanding of the molecular mechanism responsible for the resistance to the outflow facility. In a recent study, a carbohydrate-binding protein, E-selectin (ELAM-1, CD62E), was identified as a specific molecular marker of glaucoma. It was demonstrated that while E-selectin is consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes of glaucomas of diverse etiology, it was absent in the outflow pathway of all normal eyes examined. We propose a unique hypothesis that TM cell surface E-selectin, by binding to its putative glycoprotein counterreceptors on adjacent cells or in aqueous humor activates key signaling pathways, which in turn, by promoting cell-matrix and/or cell-to-cell interactions and cytoskeletal changes, provide a protective stress response specific to the aqueous outflow pathway of the eye. In this NEI R03 application, we propose pilot studies to determine whether the hypothesis merits a detailed investigation.
In Aim 1, using immunohistochemical and Western blot analysis, we shall establish which specific carbohydrate ligands of selectins, if any, are expressed on the TM cells and in the aqueous humor of normal and glaucomatous eyes.
In Aim 2, we shall determine whether the selectins/carbohydrate-mediated signaling promotes adhesion of TM cells to a variety of extracellular matrix molecules in vitro. The proposed studies will determine whether the selectin-based carbohydrate recognition system plays a role in the pathogenic mechanisms of aqueous outflow resistance in glaucoma.
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