THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. The activation of immune effector cells at sites of inflammation, such as arthritic synovium, plays an important part in autoimmune diseases. Our long term goals are to understand the molecular mechanism of the activation of monocytes and T cells which are recruited to inflammatory synovium, and the consequences of activation for pathogenesis of disease. Our experiments have shown that inflammatory synovial fluids (SFs), obtained from patients with active arthritis, activate the monocyte effector genes FcgammaRI, FcgammaRIII, and HLA DR, and skew T cell cytokine production toward a T helper 2 (Th2) pattern. These SF effects are mediated, in part, through activation of the Jak-STAT pathway, a major intracellular signaling pathway that links signals generated by numerous cytokines with transcriptional activation of target genes. Activation of the Jak-STAT pathway by SFs and IL-6 was inhibited by CAMP, the calcium ionophore ionomycin, and GM-CSF. Greater understanding of the regulation of transcriptional responses to inflammatory stimuli will be useful in developing novel approaches to suppress inflammatory processes. Therefore, our specific aims are: (1) To characterize the mechanisms of transcriptional activation of monocyte effector genes by inflammatory SFs. (2) To examine the regulation-of STAT transcription factors during T cell activation and development of TH1 and TH2 cytokine responses. (3) To identify the mechanism(s) by which cAMP, ionomycin, and GM-CSF inhibit the activation of STATs by IL-6 and SFs. The knowledge gained from these studies will enhance our understanding of the pathogenesis of inflammatory arthritis, and can be used to design specific therapeutic interventions which inhibit central activation pathways and suppress multiple inflammatory effector mechanisms.
