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DURHAM, N.C. - A multidisciplinary team of Duke University Arthritis Center researchers will spend the next four years piecing together possible answers to the puzzling disease rheumatoid arthritis with the support of a $4.3 million grant from the National Institutes of Health.

As the nation's sole Specialized Center of Research (SCOR) in rheumatoid arthritis, the Duke center is taking a four-prong approach to understanding the basic mechanisms that trigger joint destruction in the chronic inflammatory disease that affects 1 million to 2 million Americans.

"The idea behind a center-based approach is to bring scientists and clinicians together to try to understand the key steps in disease," said Dr. David Pisetsky, in announcing the award Tuesday. He is the primary investigator for the overall study and chief of rheumatology, allergy and clinical immunology at Duke.

"Each of the four projects under the grant has a physician and a basic researcher to try to use new techniques to address clinically relevant research. We want to both understand the disease process and find new therapies for patients."

The studies involve researchers from rheumatology, immunology, hematology, orthopedics and biomedical engineering, all focused on the critical steps in the activation and migration of immune cells to the joint, Pisetsky said. The current study builds on Duke research conducted under SCOR grants the past 10 years.

"It is a wonderful achievement for Dr. Pisetsky, his team and the arthritis center at Duke to be the national leader in this effort," said Dr. Barton Haynes, chairman of the department of medicine.

"Rheumatoid arthritis is an immune system disease that is very complex, where a number of pieces of the body's defense system target the wrong tissue as 'the enemy.'

We're trying to find different molecules involved in the process and better ways to block this assault," Pisetsky explained.

The first project, led by Haynes and Dr. Larry Liao, focuses on the molecules that regulate trafficking of cells to the joints and the interaction between cells and joint tissue. The researchers will continue to explore the role of CD44, a receptor found on T cells in the joint fluid, in the inflammation process. Previous studies have indicated elevated levels of the receptor are tied to increased inflammation and build up of cells in joint tissue, leading to eventual joint damage. By studying the progress of the disease in mice genetically engineered to lack CD44, the researchers hope to determine if anti-CD44 therapy could become an effective weapon against rheumatoid arthritis.

The second project explores the relationship between rheumatoid arthritis and nitric oxide, which has been found in high levels in affected joints. Arthritis researcher Dr. Brice Weinberg and Farshid Guilak, a biomechanical engineer in orthopedics, will study biomechanical stress on cartilage in the joints as a possible contributing factor, rather than a result, of overproduction of nitric oxide. The research could lead to a better understanding of how joint use can affect progression of rheumatoid arthritis.

Adhesion molecules, a group of proteins connected to early stages of immune cell migration to the joint, are targeted in the third project of the SCOR study. Pisetsky and immunology researcher Thomas Tedder hope the study of mice in which a gene has been eliminated, resulting in a lack of adhesion molecules, will lead to an understanding of the development of lesions in the rheumatoid joint. The research could advance the development of a safe therapy to block this migration of immune cells.

The fourth project under the SCOR grant works with elements of two of the other projects. Dr. Dhavel Patel and Haribabu Bodduluri will study the array of chemokines and chemokine receptors in the joint and their role in regulating cell activity that results in joint inflammation. Chemokines are thought to be key in the process of the firm adhesion of leukocytes, or white blood cells, to blood vessels before their migration into the joint tissue. The researchers will be looking at the impact of chemokines on adhesion molecules and how chemokines alter the function of CD44.