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Researcher Gets $1.7 Million for Eye Study

A researcher in the USC School of Pharmacy has received a National Institutes of Health renewal grant of $1.7 million to study the function of the lacrimal gland � a key moisture-producing gland located just above the eye.

“This grant renewal allows us to continue our scientific investigation of the normal secretory process, which will enable us to pinpoint the cause of dry eye at the cellular level,” said Sarah Hamm-Alvarez, Gavin S. Herbert Professor and associate professor of pharmaceutical sciences who was awarded the NIH grant.

Tears are comprised of water, lipids and proteins critical for sealing in essential nutrients. With each blink, the eyelid spreads tears over the surface of the eye.

A person with dry-eye syndrome experiences constant pain and a sandy or gritty feeling that, if left untreated, can lead to scarring of the cornea or loss of vision.

“Approximately 10 million people [in the U.S.] are afflicted with dry-eye syndrome, primarily post-menopausal women,” Hamm-Alvarez said. “Fluctuating levels of estrogen contribute to changes in the lacrimal gland that affect moisture production. In addition, specific cellular malfunctions can contribute to this problem.”

An autoimmune disorder called Sj�gren’s Syndrome causes the body’s immune system to attack its own moisture-producing glands, leaving the eye without adequate tears. As many as 4 million Americans may suffer from the disease.

According to Hamm-Alvarez, a complex framework called the cytoskeleton gives the cell shape and support, allowing motor proteins to move back and forth along these structures or be “trafficked” back and forth.

The motor proteins carry the secretory vesicles full of tear fluid and allow them to be packaged and released at the membrane wall. Only then can a tear be shed.

After the tear is released, the membrane has to be recycled to get ready to produce more tear fluids for release.

“With Sj�gren’s Syndrome, we believe that there is a problem with the protein trafficking, which causes an autoimmune response,” she said.

After working with a number of different mouse models, Hamm-Alvarez has discovered a bioengineered strain of mice that seems to be the ultimate model for studying the molecular mechanism responsible for tear secretion.

“The non-obese diabetic (NOD) mouse develops Sj�gren’s independently of its diabetes and shows major changes in the secretory pathway as early as one month after birth,” Hamm-Alvarez said.

The fact is significant, said the researcher, because most studies of Sj�gren’s have focused on a lacrimal gland that has lost the ability to secrete and is already subject to major inflammatory responses.

“With the NOD mouse, we can identify what actually contributes to these early changes in secretory membrane traffic, and ultimately, pinpoint the cause of secretory deficiency,” Hamm-Alvarez said.

The acquisition of a new imaging system equipped with multiphoton and conventional lasers �awarded by the National Eye Institute � allows Hamm-Alvarez to view the changes.
“We take live cells from the lacrimal gland and introduce proteins that have been fluorescently modified,” she said. “Under a microscope, we can watch the cells secrete in ‘real time’ and understand how changes in function of different proteins affect the process.

“Our goal is to determine if the immune system’s attack on the lacrimal gland causes problems with secretion, or if early changes in the lacrimal gland trigger the immune response that results in the development of Sj�gren’s Syndrome,” Hamm-Alvarez said. “We think it’s the latter.”

Researcher Gets $1.7 Million for Eye Study

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