Ae-Kyung Yi, PhD, associate professor in the Departments of Pediatrics, and Microbiology, Immunology and Biochemistry at the University of Tennessee Health Science Center (UTHSC), has received a grant totaling $1.6 million from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a subsidiary of the National Institutes of Health. The award will be used to support a project titled, “TLR/IL-1R Signaling Intermediaries and a Target-Specific Therapeutic for Arthritis.” The award will be distributed over a five-year period.
Rheumatoid arthritis is a chronic and crippling autoimmune disease with destructive inflammation in joints that affects one to two percent of the population. Because of the unknown causes and complexity of rheumatoid arthritis, as well as the multiple mechanisms and pathways that are involved in the disease process, there is no cure. Many treatments that are currently available have limited usefulness and/or undesirable side effects.
The long-term objectives of Dr. Yi’s research program are to understand the biochemical mechanisms of signaling pathways involved in innate immune responses, and the contribution of these responses to the development of acute and chronic inflammatory diseases. Her research team is currently investigating the biochemical mechanisms of an enzyme called “protein kinase D1 (PKD1)” that is involved in the molecular signaling pathways of innate immune cells that play a critical role in the damaging inflammatory processes in arthritic joints. They are developing pathway-specific and target-specific therapeutic strategies to interrupt this vicious and self-reinforcing cycle in joints using nanotechnology (the creation and use of extremely small structures).
Previous studies in Dr. Yi’s laboratory identified PKD1 as an essential signaling intermediary in the immune responses that cause inflammation. Recent research efforts by her team, which were made possible by a support from the Arthritis Foundation, suggest that PKD1 is one of the critical factors for development of inflammation in the joints of susceptible individuals, and can be a valuable target for therapeutic intervention. They have shown that the inhibition of PKD1 function in a specific signaling pathway is possible, without affecting other important pathways, and that this inhibition results in much less inflammation in joints and has fewer adverse effects than currently available treatments.
The grant award will be used to further identify the precise mechanism of PKD1 in the inflammation process, develop pathway-specific PKD1 inhibitors as therapeutic agents, and to deliver the agents directly to painful arthritic joints using nanotechnology.
“I am very thrilled about this award because it will not only enable us to define the activation mechanism and unique function of PKD1 in this important signaling pathway, but will establish the mechanisms by which an early signaling event initiates and perpetuates a chronic inflammatory process in joints. It will also provide new insights into how this pathway can be targeted for suppression — providing the opportunity to develop novel and specific therapeutic approaches to rheumatoid arthritis and other complex autoimmune diseases,” said Dr. Yi. “We anticipate that our work will lead to a new therapeutic option for arthritis patients that is more effective and much safer –having fewer side effects than many traditional therapies.”
The National Institutes of Health (NIH), the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.