Mitogen activated protein kinases (MAPKs) are serine/threonine kinases that mediate signal transduction and orchestrate cellular responses to environmental stress. In mammalian cells, three principle MARK pathways have been identified, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MARK. p38 MARK is especially relevant to rheumatoid arthritis (RA) because it regulates cytokines as well as proteases that participate in extracellular remodeling. P38 is activated via phosphorylation by upstream MARK kinases (MKKs), such as MKK3, MKK4, and MKK6. Preliminary studies suggest that MKKS plays a key role in TNF-mediated synoviocyte activation and that MKKS deficiency blocks synovitis in a mouse model of arthritis. However, in vitro and in vivo responses to Toll-like receptor ligands like endotoxin are normal. We propose to test the hypothesis that selective inhibition of specific MKKs can suppress pathogenic inflammation with relative sparing of innate immunity. We plan to determine the 1) the role of MKKs in mouse models of arthritis and inflammation using MKK knockout mice;2) phosphorylation patterns and signaling complex formation of MKKS, MKK4, and MKKS in cultured synoviocytes;and 3) the function of these MKKs in synoviocytes, including kinase knockdown experiments and assessment of the differential effects of cytokines compared with Toll-like receptor ligands;3) the upstream MKK kinases that are responsible for MKK activation in vitro. These studies will provide detailed information on the mechanism of p38 activation in inflammatory arthritis and test the hypothesis that selective targeting of MKKs like MKKS will be beneficial in RA.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-HAI-K (09))
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Peyman, John A
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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