Rheumatoid arthritis (RA) is a chronic autoimmune arthritis, characterized by synovitis, pannus formation and periarticular erosions. The mechanisms underlying disease initiation and progression in RA remain poorly understood. Tyrosine kinases play a central role in the activation of signal transduction pathways and the cellular responses that mediate the pathogenesis of RA. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr-Abl expressing leukemias. We recently demonstrated that imatinib potently prevents and treats collagen-induced arthritis (CIA) in mice. We showed that micromolar concentrations of imatinib abrogated multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNFalpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFRbeta signaling and proliferation. This application is to further characterize the relative roles of these pathways in RA. Our overriding hypothesis is that one or more of these signal transduction pathways and its downstream cellular responses contribute to initiation and progression of autoimmune arthritis. To investigate this hypothesis, we will explore inhibition of PDGFR, c-Kit, c-Fms, and c-Abl by testing small molecule kinase inhibitors in the collagen-induced arthritis (CIA) model for RA. We will perform immunohistochemistry on joint tissue derived from mice with CIA and human RA patients to characterize the in situ expression, activation and cellular distribution of PDGFR, c-Kit, c-Fms and c-Abl. Finally, we will apply phospho-protein flow cytometry to characterize the activation states of kinases and signaling pathways in mast cells, fibroblast-like synoviocytes, synovial macrophage, and B cells derived from human RA and OA synovial tissue. Success of the proposed studies will advance our understanding of the mechanisms underlying the pathobiology of RA, and could lead to clinical trials of selective tyrosine kinase inhibitors in RA. Relevance to public health: Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects 0.6% of the world population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. Tyrosine kinase inhibition represents a promising new therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054822-04
Application #
7626270
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$295,291
Indirect Cost
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Robinson, William H; Lindstrom, Tamsin M; Cheung, Regina K et al. (2013) Mechanistic biomarkers for clinical decision making in rheumatic diseases. Nat Rev Rheumatol 9:267-76
Sokolove, Jeremy; Brennan, Matthew J; Sharpe, Orr et al. (2013) Brief report: citrullination within the atherosclerotic plaque: a potential target for the anti-citrullinated protein antibody response in rheumatoid arthritis. Arthritis Rheum 65:1719-24
Sokolove, Jeremy; Lindstrom, Tamsin M; Robinson, William H (2012) Development and deployment of antigen arrays for investigation of B-cell fine specificity in autoimmune disease. Front Biosci (Elite Ed) 4:320-30
Swanson, Christina D; Akama-Garren, Elliot H; Stein, Emily A et al. (2012) Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis. J Immunol 188:3513-21
Sokolove, Jeremy; Zhao, Xiaoyan; Chandra, Piyanka E et al. (2011) Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fc? receptor. Arthritis Rheum 63:53-62
Paniagua, Ricardo T; Fiorentino, David F; Chung, Lorinda et al. (2011) Tyrosine kinases in inflammatory dermatologic disease. J Am Acad Dermatol 65:389-403
Crespo, Oliver; Kang, Stacey C; Daneman, Richard et al. (2011) Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis. J Clin Immunol 31:1010-20
Lindstrom, Tamsin M; Robinson, William H (2010) Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc 58:1565-75
Lindstrom, Tamsin M; Robinson, William H (2010) A multitude of kinases--which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin North Am 36:367-83
Paniagua, Ricardo T; Chang, Anna; Mariano, Melissa M et al. (2010) c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. Arthritis Res Ther 12:R32

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