The goal of this project is to understand the mechanisms that lead to CD4 T cell activation in the absence of conventional CD28 costimulation. T cells that express a functional receptor tyrosine kinase (fibroblast growth receptor-1, FGFR-1) are increased in chronic inflammation associated with cardiac allograft rejection and rheumatoid arthritis. Engagement of the T cell receptor plus fibroblast growth factor - 1 (FGF-1) costimulation results in increased IL-2 production, and induction of AP-1 and NF-kB transcription elements. In the first aim, shared pathways in CD28 and FGFR-1 mediated T cell activation will be elucidated through studies of NF-kB induction. These studies will utilize electrophoretic mobility shift assays and supershifts to determine unique Rel/NF-kB members induced by FGFR-1. Furthermore, novel Jurkat T cells with non-functional NF-kB pathways will be utilized to directly demonstrate the requirement of NF-kB induction for FGF- mediated T cell activation. In the second major aim, the role of FGF-1 signaling in T cell differentiation and effector function will be determined by examining the relationship of FGFR-1 stimulation with differentiation into TH1 or TH2 subsets. These studies will be extended by using mice transgenic for reporter genes driven by IL-4 and IFN-Y promoter elements to determine how FGF-1 regulates TH1/TH2 activation or repression. The third major aim will characterize the role of FGFR-1 action in T cell development and disease using transgenic mice with a non-signaling, dominant negative FGFR-1 targeted to the thymus and peripheral T cells. This transgenic model will be applicable to future investigations of FGF-1 responsive T cells in a variety of disorders, including inflammatory arthritis, tumor biology, and allograft rejection. The availability of these transgenic animals will provide a resource for this Mentored Clinical Scientist Development Award to evolve into an independent project.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Gretz, Elizabeth
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Byrd, Victor M; Kilkenny, Dawn M; Dikov, Michael M et al. (2003) Fibroblast growth factor receptor-1 interacts with the T-cell receptor signalling pathway. Immunol Cell Biol 81:440-50
Thomas, J W; Thieu, T H; Byrd, V M et al. (2000) Acidic fibroblast growth factor in synovial cells. Arthritis Rheum 43:2152-9
Byrd, V M; Ballard, D W; Miller, G G et al. (1999) Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. J Immunol 162:5853-9