June 20, 2008

Studies track pressure’s role in optic nerve degeneration

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David Calkins, Ph.D., examines a slide in his lab. (photo by Neil Brake)

Studies track pressure’s role in optic nerve degeneration

Researchers at Vanderbilt Medical Center have discovered that glaucoma, which slowly robs a person of eyesight, might actually begin with damage in the brain.

With the aid of recent grants totaling $2.2 million, David Calkins, Ph.D., and colleagues are studying how pressure in the eye translates to optic nerve degeneration and loss of communication in the brain.

Calkins hopes the most recent discovery will serve as a helpful tool for tracking the disease and testing future therapies.

“My lab focuses on how ocular pressure kills retinal ganglion cell neurons whose axons form the optic nerve,” said Calkins, associate professor of Ophthalmology and Visual Sciences, Neurosciences and Psychology. “The optic nerve connects the retina to the brain. We have found a novel class of receptor expressed by retinal ganglion cell neurons and their axons that responds to pressure directly.

“The activation of this receptor by pressure causes an increase in calcium that, in turn, sets into motion a cascade that results, first, in a loss of axon function and later in large scale degeneration of the optic nerve.”

Calkins explained that calcium is important in cell signaling and is normally present in high levels for a multitude of functions in both the eye and the brain. What his team doesn't understand is how calcium “goes from being a good thing to being involved in the degenerative process.”

One of Calkins' goals is to find a way to intervene in the disease process as early as possible to prevent this level of deterioration. Once axons and neurons in the brain are damaged beyond a certain point, they do not grow back. The retina and optic nerve are part of this network.

“The pressure receptor may be involved in a very, very early disease process in the optic nerve,” explained Calkins, also a member of the Vanderbilt Brain Institute.

That process results in the loss of communication between the end of the optic nerve and the visual centers of the brain. The brain has a very particular response to this loss of communication: It increases the level of a particular growth factor called brain derived neurotrophic factor, or BDNF, which is believed to help boost communication between the brain and the surviving terminals from the optic nerve.

“The brain is trying like crazy to preserve its own visual activity,” Calkins said. “BDNF slows the progression, but we don't think it restores dead connections. We are working on ways to enhance this natural BDNF response.”

The research team work is in pre-clinical stages, using animal models. It hopes to move into the clinical trial domain in the next five years.

“The retina of the eye has an intrinsic sensitivity to pressure, and our work focuses on trying to diminish that sensitivity by pharmacologically blunting the response to that pressure-sensing receptor.”

Glaucoma is the leading cause of irreversible blindness in the world.