CLEVELAND--A dart-like molecule that adheres to proteins in the eye is the key that turns on the uncontrolled growth of blood vessels, according to researchers at Case Western Reserve University and the Cleveland Clinic Cole Eye Institute. Uncontrolled blood vessel growth is a major contributor to the development of age-related macular degeneration (AMD), the leading cause of blindness among people over 65 in the United States.
Robert Salomon and his graduate students Kutralanathan Renganathan and Liang Lu of Case's Department of Chemistry in the College of Arts and Sciences, found that the molecule, Carboxyethylpyrroles (CEPs), attaches to proteins found in the eye, triggering the uncontrolled growth of blood cells.
The Case researchers teamed up with Quteba Ebrahem Jonathan Sears, Amit Vasanji, John Crabb and Bela Anand-Apte and Xiaorong Gu (a Salomon group alumna), of Cleveland Clinic, to complete the study titled Carboxyethlpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration."
The results of their collaborative work were published in the recent Proceedings of the National Academy of Science (PNAS).
AMD is a progressive disease that results in the severe loss of vision. The early stages of AMD are characterized as "dry," with the disease advancing to the "wet form" as the retina, the part of the eye responsible for central vision, becomes infused with fluid from leaky new blood vessels, during a process called neovascularization. The unchecked blood vessel growth, or angiogenesis, in the retina accounts for 80% of the vision loss in the advanced stages of AMD.
The retina cells that detect light contain polyunsaturated fatty lipids that are exquisitely sensitive to damage by oxygen. Even in healthy eyes, these cells are renewed every ten days. The researchers at Case and Cleveland Clinic used a method developed by Salomon to specifically detect and measure the amount of CEPs found in the eye.
The researchers did in vivo animal studies with membranes from chicken eggs and rat eyes and found that CEPs attached to proteins induce angiogenesis. They also found that the protein part of CEP-protein adducts is not important for producing the growth of the blood vessels. Rather, the actual CEP is the cause of angiogenesis.
In an attempt to block CEP from triggering the angiogenesis process, "we are now trying to find the receptors – the keyholes – in the retina cells that are activated by CEPs," said Salomon. "We are also designing drugs that can mop up the CEPs or prevent their formation."
The research is supported by an Ohio Board of Regents Biomedical Research Technology Transfer Award to the Cole Eye Institute, National Institutes of Health Grants as well as the Foundation Fighting Blindness and the American Health Association.
For more than three decades, Salomon has worked in the area of lipid research. His work centers on the oxidation of lipids in the body that contributes to a host of diseases including glaucoma, keratitis and other eye diseases as well as Alzheimer's disease, atherosclerosis, autism and end-stage renal disease. He discovered many chemical transformations that occur as a result of lipid oxidation, and generated some of the first molecular tools that have been used in clinical studies relating the hardening of the arteries in heart disease. In the hope of preventing the formation of toxic molecules in the eye, through the combination of oxygen with lipids, Salomon is now studying the processes that generate them with a new grant from the National Eye Institute of the National Institutes of Health.
Case Western Reserve University is among the nation's leading research institutions. Founded in 1826 and shaped by the unique merger of the Case Institute of Technology and Western Reserve University, Case is distinguished by its strengths in education, research, service, and experiential learning. Located in Cleveland, Case offers nationally recognized programs in the Arts and Sciences, Dental Medicine, Engineering, Law, Management, Medicine, Nursing, and Social Work. http://www.case.edu.
The Cleveland Clinic Cole Eye Institute, under the leadership of Hilel Lewis, M.D., is ranked one of the top eye care departments in the country, according to a recent survey published by U.S. News & World Report. More than 135,000 patient visits were recorded at the Institute in 2003. The Institute has state-of-the-art eye clinics, operating rooms for eye surgery, and extensive laboratory and clinical space dedicated to research on ophthalmic diseases and development of new treatments.
Cleveland Clinic, located in Cleveland, Ohio, is a not-for-profit multispecialty academic medical center that integrates clinical and hospital care with research and education. Cleveland Clinic was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. U.S. News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. Approximately 1,500 full-time salaried physicians at Cleveland Clinic and Cleveland Clinic Florida represent more than 100 medical specialties and subspecialties. In 2005, there were 2.9 million outpatient visits to Cleveland Clinic. Patients came for treatment from every state and from more than 80 countries. There were nearly 54,000 hospital admissions to Cleveland Clinic in 2005. Cleveland Clinic's Web site address is www.clevelandclinic.org.
Journal
Proceedings of the National Academy of Sciences