Department of Ophthalmology
University of California, San Francisco (UCSF)
San Francisco, CA

BASIC RESEARCH PROJECT

Measuring fluid clearance pathways in retinal edema

Research Interests

Leakage of fluid from damaged blood vessels into the retina is the cause of vision loss in several eye diseases including macular edema and diabetic retinal edema. One potential approach to treating accumulation of fluid in the retina is to develop therapies that help it clear more quickly, but the routes of fluid clearance from the retina and the proteins that promote fluid clearance remain unknown. Here we propose to develop a new imaging method designed to measure how fluid is cleared from the retina, and use it to determine if the retinal protein aquaporin-4 is required for clearance.

Plans for 2025

The purpose of this project is to apply novel imaging techniques, that Dr. Smith’s laboratory team developed for measuring brain fluid transport, to the retina. He will use these techniques to measure the routes of fluid clearance from the retina and to determine if there are specific structural barriers to clearance. The water channel protein, aquaporin 4, is thought to be important for fluid clearance from the brain and we will do further experiments to test if aquaporin-4 regulates fluid clearance in a mouse model of diabetic retinal edema. Results of these experiments will identify new pathways and molecular targets for therapeutics designed to accelerate retinal fluid clearance.

In 2025, Dr. Smith plans to complete work on the outstanding specific aims, and will continue to develop methods for measuring extracellular fluid movement in the eye of anesthetized mice with intact and functional blood vessels. In the second aim, his lab will measure the effect of retinal inflammation on the structure of the retinal extracellular space.

Specific Aims:
Aim 1: To measure extracellular solute clearance pathways in the retina. In aim 1, the team will measure transport of fluorescently tagged molecules that have been introduced into the retina and determine if fluid can flow through the retina.

Aim 2: To characterize changes in extracellular structure that occur in response to retinal inflammation. In aim 2, the team will use a model of retinal inflammation to determine how inflammation alters fluid movement through the extracellular space of the retina.

Progress in 2024

In 2024, Dr. Smith developed novel methods for measuring fluid transport in the perivascular spaces of brain. His lab is currently continuing to develop approaches for applying these methods to the eye.

Dr. Smith proposed two new aims for 2024; the first aim is to develop methods for measuring extracellular fluid movement in the eye of anesthetized mice with intact and functional blood vessels. In the second aim, his lab will measure the effect of retinal inflammation on the structure of the retinal extracellular space.

Specific Aims: This project has two distinct specific aims for 2024: Aim 1: To measure extracellular solute clearance pathways in the retina. In aim 1, Dr. Smith will measure transport of fluorescently tagged molecules that we have introduced into the retina and determine if fluid can flow through the retina. Aim 2: To characterize changes in extracellular structure that occur in response to retinal inflammation. In aim 2, Dr. Smith will use a model of retinal inflammation to determine how inflammation alters fluid movement through the extracellular space of the retina.

Progress in 2023

In 2023, Dr. Smith’s laboratory completed experiments which demonstrate that spaces surrounding blood vessels in the retina play a key role in removing fluid from the retina and that these spaces connect the central regions of the retina with the surface. the team did not find evidence for a role of the glial water transporter aquaporin-4 in regulating fluid transport along these pathways in the healthy eye and they are currently completing studies to determine if aquaporin-4 regulates fluid movement in the diabetic eye.