Reduced drainage of aqueous humor (AH) from the eye through the conventional outflow pathway underlies the ocular hypertension in the blinding disease primary open angle glaucoma. Currently, the biology and biomechanics behind conventional outflow and intraocular pressure regulation are poorly understood. The overall goal of this application is to understand how shear stress regulates resistance to aqueous flow into Schlemm's canal. Hypothesis: As intraocular pressure increases, the Schlemm's canal compresses or partially collapses, resulting in increased shear stress from AH flow. Schlemm's canal inner wall cells sense this shear stress and respond with decreased endothelin-1 (ET-1) and increased nitric oxide (NO) production. Background: Substantial evidence shows that in conventional outflow, resistance to AH flow is highest at the juxtacanalicular trabecular meshwork and inner wall of the Schlemm's canal. The cells here produce ET-1 and express the NO producing enzyme nitric oxide synthase but the mechanism(s) controlling their production are unknown. In the vasculature, there is a well characterized mechanism where vascular endothelial cells sense shear stress and adjust their ET-1 and NO production. The Schlemm's canal cells are vascular in origin and integrity of cell-cell junctions in the Schlemm's canal affects AH permeability and outflow resistance. In the vasculature, one effect of NO is increased endothelial permeability, which is attenuated by ET-1. We hypothesize that the ratio of ET-1 to NO affects aqueous permeability in the Schlemm's canal. In this study, we will determine how shear stress in the conventional outflow pathway affects ET-1/NO production and determine how shear stress affects permeability of the Schlemm's canal inner wall.
This project is designed to uncover the biofluid mechanics of intraocular pressure regulation a critical but poorly understood component. The results from this project will provide a needed step toward understanding the physiology of conventional outflow and the dysfunction behind open angle glaucoma.
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