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Arthritis and Immunology Research Program

Dr. Sawalha In The News

OMRF receives $26 million for two federal research grants

OMRF researcher finds genetic links for rare and deadly disease

Amr H. Sawalha, M.D. Assistant Member, Arthritis and Immunology Research Program Assistant Professor of Medicine, Department of Medicine, University of Oklahoma   Health Science Center Staff Physician, U.S. Department of Veterans Affairs Medical Center, Oklahoma City Adjunct Assistant Professor, Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City

Research Interests
My work focuses on studying the pathogenesis of systemic lupus erythematosus, a chronic autoimmune disease that affects multiple organ systems. Our current knowledge provides evidence for both genetic and environmental factors involved in the pathogenesis of this disease. Over the last decade, a large body of evidence has accumulated that implicates abnormal DNA methylation in T cells as a potentially important etiologic factor for lupus. In fact, overexpression of a number of methylation-sensitive genes in lupus T cells, such as CD11a, CD70 and perforin, makes T cells autoreactive and capable of providing B-cell help in the absence of antigenic stimulation. B cells interacting with such autoreactive T cells were shown to produce antibodies, the hallmark of lupus. Causes of defective T-cell DNA methylation in lupus are unknown.

My current work focuses on the role of the MEK/ERK signaling pathway in the regulation of T-cell DNA methylation in lupus. DNA methylating enzymes, especially dnmt1, are in part regulated by MEK/ERK signaling. We are therefore developing a transgenic mouse line that overexpresses a dominant negative MEK in T cells. These mice show reduced dnmt1 expression and overexpression of the methylation-sensitive genes in T cells. In addition, female mice expressing dominant negative MEK develop anti-dsDNA antibodies that are lupus specific.

My lab will continue to characterize this murine lupus model as well as use it to test new treatments for the disease. We plan to pursue genetic studies on various candidate genes regulating the MEK/ERK pathway and DNA methylation in lupus patients.

Another methylation-sensitive gene, CD40L, is overexpressed only in our female transgenic mice, and only these females develop anti-dsDNA antibodies. This finding forms the basis for another important focus of my research. Interestingly, the CD40L gene is located on the X chromosome, which allows significantly higher expression in females if both copies of that gene are hypomethylated as opposed to the single copy in males. This finding may explain the predominance of lupus, and perhaps autoimmunity, in females. Understanding this aspect of the disease, and the pathways behind the abnormal DNA methylation in lupus patients will likely provide new targets for therapeutic interventions

Joined OMRF Scientific Staff in 2005.

Mailing Address
Arthritis and Immunology Research Program, MS 24
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-7977
Fax: (405) 271-4110
E-mail: Amr-Sawalha@omrf.org