(verbatim from application) The long term objective of this work is to better understand the molecular mechanisms of T cell dysfunction in elderly humans. Recent findings show that T cells from substantial proportions of elderly humans exhibit impairments in the activation/phosphorylation of TCR/CD3-CD4 associated Fyn and Lck protein tyrosine kinases and ZAP-70/phospho-zeta-chains. Other studies provide direct evidence that aging can lead to diminished activation of the Ras/Raf-1/MEK/ERK cascade and IL-2 production in TCR/CD3- CD4 activated human T cells.
The specific aims of this study are: (1) to investigate if aging alters the coupling or recruitment of Fyn and Lck to TCR/CD3 and/or CD4 determinants, (2) to analyze if distinct defects in the regulation of Fyn and Lck catalytic activities may contribute to age-related reductions in the phosphorylations of TCR/CD3 and CD4 immunocomplexes, (3) to evaluate if aberrant interactions between phospho-zeta-chains & ZAP-70 coincide with altered phosphorylation or recruitment of LAT and SLP-76 to TCR/CD3-CD4 immunocomplexes in elderly T cells, (4) to determine if aging perturbs the normal coordinate activation of Fyn, Lck and ZAP-70/phospho-zeta needed for Ras-ERK activation. The methodologies for investigating the Fyn, Lck, and ZAP-70 signaling kinases and the Ras/Raf-1/MEK/ERK cascade are quantitative and operational. This project will analyze age-related heterogeneity and define impairments in T cell signaling transducers among elderly humans using quantitative analyses and standard biostatistical procedures to reach valid conclusions. The results from these studies will provide new insights into the initial aberrancies of TCR/CD3-CD4 mediated signaling events and downstream signal transduction in T cells from a substantial proportion of elderly humans. Better understanding age- related changes in early TCR/CD3-CD4 mediated molecular events and kinase cascades important for the expression of IL-2 and functional competence of T cells will advance our knowledge of the immunobiology of human aging. Furthermore, new information about the molecular mechanisms of these changes may be applied to clinical problems and facilitate more effective vaccines and treatments to reduce the considerable morbidity and mortality due to infectious diseases and other disorders of elderly humans.
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|Whisler, R L; Chen, M; Liu, B et al. (1999) Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59fyn/p56lck in human T cells. Mech Ageing Dev 111:49-66|
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|Whisler, R L; Karanfilov, C I; Newhouse, Y G et al. (1998) Phosphorylation and coupling of zeta-chains to activated T-cell receptor (TCR)/CD3 complexes from peripheral blood T-cells of elderly humans. Mech Ageing Dev 105:115-35|
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|Liu, B; Carle, K W; Whisler, R L (1997) Reductions in the activation of ERK and JNK are associated with decreased IL-2 production in T cells from elderly humans stimulated by the TCR/CD3 complex and costimulatory signals. Cell Immunol 182:79-88|
|Whisler, R L; Bagenstose, S E; Newhouse, Y G et al. (1997) Expression and catalytic activities of protein tyrosine kinases (PTKs) Fyn and Lck in peripheral blood T cells from elderly humans stimulated through the T cell receptor (TCR)/CD3 complex. Mech Ageing Dev 98:57-73|
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