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Joslin Researchers Discover Protein that Causes Blood Vessel Leakage in Eyes with Diabetic Retinopathy

January 30, 2007
Although health professionals have had success in treating diabetic retinopathy, two forms of the disease — proliferative diabetic retinopathy and diabetic macular edema — still are the leading causes of vision loss and blindness among working age adults in the developed world. Now a Joslin Diabetes Center-led team of investigators has compiled the most complete inventory yet available of the proteins present in a part of the human eye known as the vitreous and has identified a group of proteins that may play critical roles in causing blood vessel leakage in the eyes of people with this common form of diabetic eye disease.

In the new study, published in the Jan. 28 online edition of the journal Nature Medicine, lead investigator Edward Feener, Ph.D., and his team also found that one of these molecules causes the leakage of retinal blood vessels, which contributes to the retinal swelling (diabetic macular edema or DME) that is often associated with advanced diabetic retinopathy. These findings suggest potential new therapeutic targets for the treatment of diabetic retinopathy and DME and also could provide new opportunities for treating cerebral swelling caused by head injury, stroke and other conditions.

"By analyzing the protein composition in the human vitreous (the gel fluid that fills the cavity of the eye between the lens and the retina), we have identified a new group of molecules that may improve our understanding of the disease processes that contribute to diabetic retinopathy. By studying the actions of these proteins in both the retina and the brain, we have shown that our findings may have broad relevance for neurovascular leakage and swelling," said Dr. Feener, Investigator in Joslin's Section on Vascular Cell Biology, Director of Joslin's Proteomics Core, which hosted the study, and Assistant Professor of Medicine at Harvard Medical School.

The work was funded by grants from the Juvenile Diabetes Research Foundation (JDRF), the Massachusetts Lions Eye Research Fund, the National Institutes of Health, the Adler Foundation, and the Air Force Office of Scientific Research Medical Free Electron Laser Program.

"Millions of people worldwide live with diabetic retinopathy and the accompanying threat of severe vision loss or blindness. While some treatment is available in the late stages of this condition, the incidence of proliferative diabetic retinopathy and diabetic macular edema still pose the serious threat of sight loss. Going forward, Dr. Feener's findings could provide new opportunities for the development of treatments for diabetes-related vision loss," said Dr. Helen Nickerson, Scientific Program Manager for Complications at JDRF.

Diabetic retinopathy, one of the most common complications of diabetes, is characterized by a range of abnormalities that develop from the damage caused by high blood glucose levels on the small blood vessels of the retina. Proliferative diabetic retinopathy (PDR) is diagnosed when the retina begins to form new blood vessels to counteract this damage, new vessels which in turn often bleed and blur or block vision. More than 700,000 patients in the United States have PDR, and more than 63,000 patients develop it annually. Diabetic macular edema occurs as the leaky blood vessels cause the macula (the central area in the retina responsible for sharp central vision) to swell. DME affects more than 500,000 patients in the U.S., with 56,000 new cases diagnosed yearly.

In the past, researchers have had difficulty studying the pathology of both of these diseases because rodents with diabetes, which investigators often use as a laboratory model to study diabetic eye disease, do not naturally produce many of the changes in the retina that health professionals observe in humans. Dr. Feener and his colleagues developed cutting edge proteomics mass spectroscopy (a high-speed protein analysis technology) and bioinformatics at Joslin to identify protein abnormalities in the vitreous of people with and without diabetic eye disease. Then, they introduced these same proteins in the vitreous of rodents and examined their effects on retinal blood vessels to gain better understanding of the actions that these proteins could have in the eyes of people with diabetes.

Working with a network of collaborators at Joslin's Beetham Eye Institute and the Santa Barbara Cottage Hospital Eye Center in California, they obtained samples from the vitreous of 25 people undergoing surgery for a variety of conditions: eight of the patients did not have diabetes and therefore no diabetic eye disease; four had diabetes, but no diabetic retinopathy; and 13 had PDR. Launching a large-scale survey of the proteins in the vitreous, they identified 117 proteins (earlier attempts to catalog vitreous proteins had succeeded in identifying only 20 to 50) and detected 31 proteins that were present in the vitreous of patients with diabetes but weren't present in people without the disease.

One of the proteins that was particularly interesting was carbonic anhydrase 1, or CA-1. "This is an enzyme that is normally found in red blood cells; however we suspected that high levels of this protein in the vitreous fluid might cause problems," said Dr. Feener. "When we tested it in the vitreous of rodents, we found a marked increase in blood vessel leakage, which is a fundamental process in diabetic retinopathy."

Margaret Dunn, President of the Massachusetts Lions Eye Research Fund, Inc., said, "On behalf of the Lions of Massachusetts and the Massachusetts Lions Eye Research Fund, Inc., we wish to congratulate Joslin Diabetes Center on its important breakthrough. We pledge our full support now and in the future in the hope that we will be able to contribute to many future endeavors of the Joslin research team and applaud them on their wonderful accomplishments."

The mission of the Massachusetts Lions Eye Research Fund (MLERF) is to fund efforts in eye research that may one day lead to the prevention of blindness in the world. They play a unique role in eye research efforts, enabling avenues of research to be explored as preliminary studies that may ultimately lead to remarkable breakthroughs in our understanding of the causes of blindness. In this respect, the research team at Joslin's Beetham Eye Institute led by Sven-Erik Bursell, Ph.D., and Allen Clermont, M.S., were able to use funding from the MLERF to conduct the necessary experiments to characterize the physiological effect of these proteins and how they were exerting these abnormal effects.

The researchers then investigated several different lines of study and found that CA-1 increased retinal edema—the swelling of the retina. "This is the first evidence we have of a protein causing swelling, not just leakage, in the rodent at concentrations observed in human disease," said Dr. Feener.

Performing additional studies with CA-1, the researchers showed that their findings have even broader relevance. "The eye is a neurovascular tissue with certain features similar to those of the brain, and it is well known that hemorrhage in the brain, either from a hemorrhagic stroke or any cerebral bleeding, causes swelling," said Dr. Feener. "When we introduced CA-1 into the cerebral spinal fluid around the brain of rodent animal models we found that it also increased the swelling and the leakage of blood vessels in the brain." This discovery, he explained, could provide new opportunities for treating the cerebral swelling caused by head injury, stroke and other conditions.

"Proteomics of human vitreous fluid has generated new ideas about the effects of diabetes on the retina," said Dr. Feener. "Now we are in the process of exploring the role of the other proteins we have identified in the vitreous, which may provide additional insights into the mechanisms that contribute to diabetic retinopathy."

Others participating in the study included lead author, Ben-Bo Gao, Ph.D., of Joslin; additional collaborators from the Section on Eye Research and the Beetham Eye Institute at Joslin included Lloyd Paul Aiello, M.D., Ph.D., Susan Rook, Stephanie Fonda, Ph.D., Paul G. Arrigg, M.D.; Vivek Srinivasan, M.S., Maciej Wojtkowski, Ph.D., and James Fujimoto, Ph.D., of the Massachusetts Institute of Technology; and Robert Avery, M.D., of the Santa Barbara Cottage Hospital Eye Center.

Joslin Diabetes Center

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