of Work: A new program has been initiated to study the molecular basis for the decline in T cell function that accompanies aging. Based on the belief that a better understanding of the biochemistry involved in normal T cell activation and function is required in order to identify the precise changes that occur with age, studies have focused on the early membrane-proximal signaling events that occur upon T cell antigen receptor (TCR) activation in standard (non-aged) T cell model systems. An especially interesting TCR-proximal signaling molecule is ZAP-70, which is a protein tyrosine kinase that is expressed only within T cells and NK cells, and is required for T cell activation through the TCR. Of particular interest is the identification of additional signaling molecules that either perpetuate or regulate the activity of ZAP-70. Progress has been made towards this goal by the use of a two-hybrid screening protocol, which has identified four gene products that appear to specifically associate with ZAP-70. The ability of the proteins expressed by these cDNAs to bind ZAP-70 is being evaluated, as is the functional relevance of their association with ZAP-70. T cells isolated from aged animals often show a diminished capacity to cope with oxidative stress. Given observations that certain oxidative stimuli (ultraviolet light and peroxide) are able to recapitulate the signals generated by antigen engagement of the TCR, investigation of the causes of the changes in tolerance towards oxidative stress with age may provide additional insight into the biochemical changes responsible for reduced T cell function with age. By using a T cell line that lacks ZAP-70, we have begun to assess the role played by ZAP-70 in the propagation of stress signals in T cells. Preliminary results show that ZAP-70 is required in order to see activation of MAP kinases in response to oxidative stimuli.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000509-01
Application #
6160458
Study Section
Special Emphasis Panel (LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Wange, Ronald L (2004) TCR signaling: another Abl-bodied kinase joins the cascade. Curr Biol 14:R562-4
Huang, Yanping; Wange, Ronald L (2004) T cell receptor signaling: beyond complex complexes. J Biol Chem 279:28827-30
Seminario, Maria-Cristina; Precht, Patricia; Wersto, Robert P et al. (2003) PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression. Oncogene 22:8195-204
Seminario, Maria-Cristina; Wange, Ronald L (2003) Lipid phosphatases in the regulation of T cell activation: living up to their PTEN-tial. Immunol Rev 192:80-97
Wange, Ronald L (2003) The missing link(er): a return to symmetry in antigen receptor signaling? Mol Interv 3:75-8, 50
Seminario, Maria-Cristina; Wange, Ronald L (2002) Signaling pathways of D3-phosphoinositide-binding kinases in T cells and their regulation by PTEN. Semin Immunol 14:27-36
Ling, P; Meyer, C F; Redmond, L P et al. (2001) Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling. J Biol Chem 276:18908-14
Veri, M C; DeBell, K E; Seminario, M C et al. (2001) Membrane raft-dependent regulation of phospholipase Cgamma-1 activation in T lymphocytes. Mol Cell Biol 21:6939-50
Shan, X; Balakir, R; Criado, G et al. (2001) Zap-70-independent Ca(2+) mobilization and Erk activation in Jurkat T cells in response to T-cell antigen receptor ligation. Mol Cell Biol 21:7137-49
Herndon, T M; Shan, X C; Tsokos, G C et al. (2001) ZAP-70 and SLP-76 regulate protein kinase C-theta and NF-kappa B activation in response to engagement of CD3 and CD28. J Immunol 166:5654-64

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