Rheumatoid arthritis (RA) is a chronic destructive inflammatory disease of unknown etiology, which affects the joints. Histopathologic examination of the rheumatoid pannus reveals hyperplasia of synovial lining cells, along with a mononuclear cell infiltrate that includes primarily T cells. The present application proposes to examine the possibility that excessive accumulation of lymphocytes and synovial cells in the rheumatoid pannus is a result of their resistance to programmed cell death (apoptosis). The hypothesis is based on recent preliminary studies by the investigators, which uncovered a sphingomyelin pathway-mediated inhibition of Fas death signaling in lymphocytes and synoviocytes of RA patients. In addition, in preliminary studies the investigators have demonstrated a role for a Gi protein-coupled receptor-mediatred activation of phosphatidylinositol-3-kinase (PI3K) in regulating the sphingomyeline pathway. Inhibition of those mechanisms reversed the signaling aberration and restored susceptibility to Fas-mediatred cell death in previously resistant RA cells. The proposed research has four specific aims: 1. To further define the receptors involved 2. To determine the mechanisms of PI3K hyperactivity 3. To map sphingomyelin pathway defect 4. To determine clinical and HLA correlates with those signaling defects The proposed research takes a novel experimental approach to study the pathogenesis of RA, based on modern concepts in autoimmunity and cutting edge methodologies. The proposed studies will likely contribute significantly to understanding the pathogenesis of RA and, perhaps, other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046468-04
Application #
6787694
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
2001-09-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$251,038
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ling, Song; Pi, Xiujun; Holoshitz, Joseph (2007) The rheumatoid arthritis shared epitope triggers innate immune signaling via cell surface calreticulin. J Immunol 179:6359-67
Holoshitz, Joseph; Ling, Song (2007) Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC disease association? Ann N Y Acad Sci 1110:73-83
Tan, Shi-Yu; Xiao, Liqun; Pi, Xiujun et al. (2007) Aberrant Gi protein coupled receptor-mediated cell survival signaling in rheumatoid arthritis B cell lines. Front Biosci 12:1651-60
Ling, Song; Li, Zhanguo; Borschukova, Olga et al. (2007) The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res Ther 9:R5
Haas, Christian S; Creighton, Chad J; Pi, Xiujun et al. (2006) Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins. Arthritis Rheum 54:2047-60
Ling, Song; Lai, Angela; Borschukova, Olga et al. (2006) Activation of nitric oxide signaling by the rheumatoid arthritis shared epitope. Arthritis Rheum 54:3423-32
Pi, Xiujun; Tan, Shi-Yu; Hayes, Michael et al. (2006) Sphingosine kinase 1-mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells. Arthritis Rheum 54:754-64
Wu, Yanling; Zheng, Jie; Linden, Joel et al. (2004) Genoprotective pathways. Part I. Extracellular signaling through G(s) protein-coupled adenosine receptors prevents oxidative DNA damage. Mutat Res 546:93-102
Ling, Song; Wu, Yanling; Zheng, Jie et al. (2004) Genoprotective pathways. II. Attenuation of oxidative DNA damage by isopentenyl diphosphate. Mutat Res 554:33-43