The long term objective of this work is to better understand the molecular mechanisms of T cell dysfunction in elderly humans. Recent findings demonstrate that T cells from substantial proportions of elderly humans have defects in key signaling events including activation of the mitogen activated protein (MAP) kinase cascade and transcriptional factors AP-1 and NF-AT.
The specific aims of this study are: (1) to investigate if age-related aberrancies exist in the expression and activation of signaling PTKs p59fyn, p56lck and ZAP-70 in human T cells stimulated by ligation of the TCR/CD3 and/or CD4 determinants, (2) to determine whether aging may alter the expression or activation of the Ras and Raf kinase components of the MAP kinase activation cascade in human T cells, (3) to analyze if aging may uncouple the coordinated activation of ERKs and JNKs required for full induction of transcriptional regulatory proteins recognizing the proximal c-jun TRE promoter and c-fos SRE promoter elements, and (4) to investigate whether the enzymatic activity of the protein phosphatase calcineurin may be altered in human T cells during aging. The methodologies for investigating signaling kinases/phosphatases and Ras activity are quantitative and operational. This project defines the age-related heterogeneity and impairments in T cell signaling transducers among elderly humans using quantitative analyses and standard biostatistical procedures to reach valid conclusions. The results from this project will provide new information about alterations of the MAP kinase cascade and signal transduction in T cells from a substantial proportion of elderly humans. Defining age-related changes in the 'molecular events important for the expression of IL-2 and functional competence of T cells will provide insights into the immunobiology of human aging. Furthermore, understanding the mechanisms of these changes may facilitate the development of more effective vaccines and treatments to reduce the considerable morbidity and mortality due to infectious diseases and other disorders of the elderly.
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