- RA is a systemic inflammatory disease characterized by destructive synovitis that is associated with increased morbidity and early mortality. Immunosuppressive therapy does not halt joint destruction, and the primary invasive lesion is composed of hyperplastic fibroblastoid cells and neovascular tissue termed pannus. These observations and the findings that RA synovium produces growth factors with autocrine potential has led to an alternative hypothesis that the disease is due to a localized tumor-like growth and immunological lesions are secondary. One potent mesenchymal and vascular growth factor, FGF-1, is uniquely overexpresssed in RA synovium and is not detected in non-inflammatory synovium. In addition, a subset of T cells that respond to FGF-1 and express its receptor, FGFR1, is increased in the peripheral blood of RA patients. Therefore, the goal of this project is to understand how FGF-1 expression and regulatory abnormalities of its receptor, FGFR1, contribute to synovial cell proliferation and T cell infiltration in RA. The first specific aim will examine the expression and regulation of FGF-1 and its receptor in inflammatory (RA), non-inflammatory, and normal synovium. Fibroblast explants will be characterized for FGFR1 structures and their signalling via receptor tyrosine kinases. Also, it will be determined whether FGF-1 production is constitutive in outgrown RA synovial fibroblasts. To determine regulation of FGF-1, experiments will examine the capacity of multiple cytokines and growth factors to alter FGF-1 expression and mRNA splicing. The second specific aim is to understand FGFR1-mediated signalling in T cells. This will be accomplished by characterizing FGFR1 number and affinity, identification of isoforms associated with PLC-gamma tyrosine phosphorylation by the receptor, and examining regulation of IL-2 production as well as the AP-1 promoter element. Also, the mechanisms of FGFR1 activation that do not include IL-2 dependent pathways will be assessed by determining if FGF-1 promotes T cell proliferation in the presence of IL-2R blockade and if FGF-1 rescues T cells from apoptotic signals. Finally, the functional status of FGFR+ T cells from RA synvoium will assess receptor affinity, isoform, and status of receptor autophosphorylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043653-03
Application #
2769621
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1996-09-30
Project End
2000-06-30
Budget Start
1998-09-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Thomas, J W; Thieu, T H; Byrd, V M et al. (2000) Acidic fibroblast growth factor in synovial cells. Arthritis Rheum 43:2152-9