Towards a Unifying Theory for Unconventional Outflow in Mice
Glaucoma is a leading cause of irreversible blindness, affecting approximately 60 million people worldwide. All treatments for glaucoma focus on lowering pressure within the eye to stop further vision loss, but the biological mechanisms controlling eye pressure are not well understood. In order to develop better drug therapies that more successfully lower eye pressure, we must conduct studies in animals, and mice are often used for glaucoma research. However, there are unanswered questions about whether eye pressure in mice is controlled by the same mechanisms that control eye pressure in humans, neither of which are fully understood. This project will determine whether mice mimic the regulatory mechanisms of eye pressure as occur in humans, so as to establish whether studies in mice are valid for identifying new drugs to lower eye pressure in humans.
The overall goal of our research is to develop more successful therapies to lower intraocular pressure (IOP) and preserve vision in glaucoma. Developing new glaucoma therapies requires a model system that faithfully replicates the physiology or pathophysiology of IOP as occurs in humans, and many laboratories have begun using mice for this purpose. In both humans and mice, IOP is regulated by the turnover of aqueous humor, which is the clear fluid that flows through the anterior (or front) part of the eye. In humans, the majority of aqueous humor drains through the conventional outflow pathway. In mice, however, some reports suggest that the majority of drainage passes through a secondary route, known as the unconventional outflow pathway. Also there are concerns regarding the methods used to make prior measurements of unconventional outflow in mice.
If we wish to continue using mice as appropriate models of IOP regulation as occurs in humans, then it is imperative to determine the true magnitude of unconventional outflow in mice. Furthermore, while unconventional outflow typically is described as occurring independently of pressure, there is no coherent description in the literature to explain how unconventional outflow could be truly pressure-independent.
Our Specific Aim 1 quantifies the relative proportions of conventional and unconventional outflow in mice, using tracers to label the anatomical routes of flow. Specific Aim 2 examines a model that attributes the mechanism of unconventional outflow to a combination of pressure-dependent and pressure-independent flow pathways, and we experimentally modify each pathway to assess its effect on unconventional outflow. Our studies make use of a unique iPerfusion system to achieve highly accurate and reproducible fluid flow measurements in mouse eyes. Ultimately, this research will clarify the relationship between pressure dependence and anatomical routes of aqueous humor outflow, determine whether the mouse is an appropriate model for aqueous humor outflow as occurs in humans, and test a unifying theory for unconventional outflow.