Dynamic Variable Aqueous Humor Outflow and Glaucoma Therapies in the Human Eye

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Project Summary Glaucoma is a leading cause of permanent vision loss worldwide, and the only treatment is to lower intraocular pressure (IOP). IOP is governed by how aqueous humor (the fluid in the eye) exits the drainage pathways that start at the trabecular meshwork (TM) before moving into Schlemm’s canal, collector channels, an intrascleral venous plexus, and aqueous/episcleral veins. However, recent discoveries have demonstrated that aqueous humor outflow (AHO) is not static and unchanging but is more complex than a simple linear depiction. AHO shows dynamic variable behavior (or dynamic variable outflow; DVO) where it is variable with segmental regions of the eye displaying high- or low-AHO, is dynamic where AHO can spontaneously increase or decrease in different locations of the eye, and is improvable where drugs or surgeries can enhance it. Thus, this proposal aims to better study DVO by uncovering how and why AHO can be improved in certain regions of the eye. This helps understand what may have been lost in disease and what may be targeted in IOP-lowering treatments. The central hypothesis in this proposal is that glaucoma therapies work at improvable DVO regions and that by facilitating DVO research and knowing where and how this occurs, personalized glaucoma treatments can be crafted for individual patients. To accomplish this, we will utilize cutting edge structural imaging tools such as anterior segment optical coherence tomography (OCT). We will also use a method called aqueous angiography that we developed on a previous National Institutes of Health and National Eye Institute grant. Aqueous angiography allows researchers to see exactly where aqueous humor is flowing in the eye in a real-time fashion. With these tools, we will study ex vivo human eyes in the laboratory and in donor in vivo eyes to yield the most germane discoveries for glaucoma and glaucoma treatment. In Specific Aim (SA1), we will discover how DVO is regulated by studying the structural and molecular basis of segmental and dynamic AHO using imaging and screen-based tools on human donor and ex vivo eyes in the laboratory. In SA2, we will use ex vivo human eyes to study how glaucoma surgeries in different locations in the eye impact IOP lowering and what hurdles the proximal vs. distal AHO pathways present to surgical success. In SA3, we will investigate how glaucoma pharmacological drugs (currently FDA-approved drug formulations and delivery) alter DVO in ex vivo and donor eyes, specifically looking at the parts of the eye that are improved by treatment to understand why these areas had the capacity to do so. Through the results of this proposal, we will better understand the dynamic processes of how intraocular fluid leaves the eye as a way to enhance current glaucoma treatments and to create a springboard to innovate new ones.