Caveolins as Novel Mechanosensors in Aqueous Outflow

Summary

Elevated eye pressure is a major risk factor for glaucoma and this pressure is regulated by controlling the drainage of fluid from the eye. There are currently no glaucoma medications that target the major pathway of fluid drainage in the eye, yet this pathway is the source of the primary cause and progression in open-angle glaucoma. Dr. Elliott’s project is designed to test a novel mechanism by which the eye regulates fluid drainage and how this mechanism might be dysfunction in glaucoma.

Project Details

The goal of this project is to test a novel concept of how eye pressure is controlled in normal and pathological conditions. Glaucoma is a heterogeneous group of diseases that represents the second leading cause of blindness worldwide, with primary open-angle glaucoma being the most prevalent form. Elevated pressure in the eye is the major risk factor in developing primary open angle glaucoma. Eye pressure is controlled by the rate at which fluid, called aqueous humor, is produced and the speed at which this fluid drains from the eye. In the normal eye, this drainage process is tightly regulated in order to maintain optimal pressure. In many forms of glaucoma, this drainage system does not work effectively leading to elevations in eye pressure. The mechanisms that tightly regulate the speed of fluid drainage are unknown, but are likely to involve a mechanical pressure sensor, similar to a thermostat, that causes drainage to increase if pressure increases and resists drainage if pressure is too low. The nature and cellular location of this "molecular thermostat" is unknown.

Recently, human gene association studies have linked the CAV1 gene with increased risk of developing primary open-angle glaucoma. This gene, which Dr. Elliott's laboratory has been studying for several years, is known to form specialized domains in cell membranes called "caveolae." There is emerging evidence that these domains may be cellular sensors for mechanical changes in cells, such as those that might result from increases in eye pressure. Dr. Elliott's team thinks that caveolae may be the sensors that regulate fluid drainage and that mutations in the CAV1 gene may render this sensor defective. Dr. Elliott has been given the BrightFocus Foundation Thomas R. Lee Award for National Glaucoma Research to test this groundbreaking idea, and also will search for the cellular location of this mechanical sensor.

The first aim of this project will address whether the membrane domains called caveolae respond to experimentally-increased eye pressure, and whether molecules associated with these membrane domains change in their location within the cells responsible for fluid drainage.
The second aim will examine the cellular location of the caveolae-dependent pressure sensor. A fundamental question in the glaucoma research field is what cell type is responsible for generating resistance to fluid drainage. Dr. Elliott's team has the unique ability to manipulate the gene necessary for caveolae formation in a cell-specific context allowing them to ask whether, for example, caveolae in the drainage vessel, called Schlemm's canal, is the site of pressure-dependent resistance to fluid drainage.

This proposed study has important translational implications as it will test a novel concept in fluid drainage outflow regulation that will provide the rationale for new therapeutic strategies for eye pressure regulation. We are indebted to the BrightFocus Foundation for its support and are honored to receive the Thomas R. Lee Award for National Glaucoma Research to help us develop this exciting project.