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Highlight on Translational Research—RAGE

Translational research is all the rage at Columbia University Medical Center. Not all the rage, perhaps, but work by the Division of Surgical Science on the Receptor for Advanced Glycation Endproducts (RAGE) represents a vitally important segment of translational research currently underway at this institution.

'Translational research' refers to biomedical investigation that advances basic science, or laboratory research, to the realm of patient therapeutics. Successful evolution of translational research requires careful, deliberate choices about which areas of laboratory research are most likely to yield practical results. Studies of a molecule called RAGE have produced such success for Ann Marie Schmidt, MD, Chief, Division of Surgical Science, Columbia University Medical Center, and her team of investigators. After several years of basic research on the molecule, Dr. Schmidt and her colleagues have reached a point where applications of this research appear likely to impact the treatment of cancer, heart disease, Alzheimer's disease, diabetes, and a host of immune-related disorders.

Dr. Schmidt's work on RAGE goes back to the 1990s, when she was conducting laboratory research on problems with blood vessels in people with diabetes. Her team made the basic discovery that sugar-modified proteins (called Advanced Glycation Endproducts, or AGEs) bind to endothelial cells (cells located on the interior surface of blood vessels), and that one particular receptor—RAGE—sends messages through cells that promote inflammation. In diabetics, inflammation contributes to serious complications including atherosclerosis, heart attacks, stroke, kidney disease, and retinopathy. "Inflammation is a key process in many lifelong diseases. RAGE does not cause diseases, but we found it is a player that perpetuates and amplifies them," says Dr. Schmidt.

In further study, Dr. Schmidt's team was surprised to learn that many inflammatory molecules (such as amyloid beta n Alzheimer's disease) interacted with RAGE. This observation gave her and Shi Du Yan, MD, Associate Professor of Clinical Pathology, an important clue that RAGE might have biological effects (such as worsening the damage caused by increased levels of amyloid-beta peptide that accumulate in the brains of people with Alzheimer's disease) and might be a worthwhile target for treatment. "It changed our view because it broadened the potential impact from just diabetes to other conditions," explains Dr. Schmidt.

Having moved from the test tube to studies on endothelial cells, Dr. Schmidt's team then designed studies of RAGE in animal models. They found that blocking the receptor markedly reduced inflammation in both large and small blood vessels. "Blockade of RAGE clearly reduced complications," Dr. Schmidt recounts. "The animals still had diabetes, tumors, and heart disease, but when RAGE was blocked, they had substantially less disease. "Her team continues to study RAGE to determine whether blocking the molecule has long term effects, and to further understand the physiological role of the receptor.

Meanwhile, their robust findings in animal studies have provided a foundation for clinical trials in people, and in conjunction with Transtech Pharma, the team developed a receptor blocker. Grants by the National Heart Lung and Blood Institute and the Juvenile Diabetes Research Foundation are supporting continued study of the biology of RAGE, its role in causing type 1 diabetes, and its role in complications of types 1 and 2 diabetes. Phase II trials are now testing whether drugs to block RAGE are safe and effective in people with Alzheimer's disease and diabetic neuropathy.

Current research on RAGE at Columbia University Medical Center

• Breast cancer: Kathie-Ann Joseph, MD
• Injury to blood vessels in diabetic patients: Shi-Fang Yan, MD, Ravi Ramasamy, MD, and Ann Marie Schmidt, MD
• Islet cell transplantation in diabetes: Kevan Herold, MD, Raphael Clynes, MD, and Ann Marie Schmidt, MD
• Liver regeneration: Jean C. Emond, MD
• Colon cancer: John D. Allendorf, MD

Future Studies

• Protect blood vessels in people with diabetes;
• Reduce other complications of diabetes including kidney disease, heart disease, and wound healing;
• Treat Alzheimer's disease;
• Delay the progression of liver disease;
• Reduce the growth of cancerous tumors;
• Enhance the treatment of rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, and other diseases.