Interleukin-2 (IL-2) is a cytokine produced by T cells that plays a very important role in the regulation of a variety of cells in the immune system. The ability of T cells to express IL-2 in response to stimuli has been shown to decrease with age in rodents and human subjects, and it appears that the age-related decrease in IL-2 expression is at least partially responsible for the age-related decline in immunological functions. Recent studies by may laboratory have shown that the age- related decline in the induction of IL-2 expression is correlated to changes in the activity of the transcription factor, NFAT; the 50 to 60% decrease in the induction of IL-2 mRNA levels and nuclear transcription of IL-2 were paralleled by a similar decline in NFAT binding activity of DNA. The transcription factor NFAT is a multi- polypeptide complex consisting of a cytoplasmic component (NFAT-C) that is T cell/IL-2 specific and a ubiquitous nuclear component (NFAT-n) that consists of c-Fos, c-June, and Elf-1 proteins. The age- related decline in NFAT binding activity that I have observed may arise from an alteration in any one of the components of the NFAT protein complex. Therefore, I plan to test the following hypothesis: the age-related decline in IL-2 gene expression arises from an alteration in one or more of the polypeptide components of the NFAT protein complex.
The specific aims of this project are as follow: 1. To determine of age-related changes occur in functional activity of either the cytoplasmic (NFAT-c) or nuclear (NFAT-n) components of the NFAT complex. 2. To determine if the cytoplasmic component of the NFAT complex (NFAT-c), e.e., NFAT-c expression, its dephosphorylation, and nuclear translocation is altered with age. 3. To determine if the nuclear components of the NFAT complex (NFAT-n), i.e., c-fos, c-jun, and elf-1 expression are altered with age. 4. To determine if changes in NFAT are responsible for the age- related changes in the induction of IL-2 transcription using a transgenic mouse model that contains a NFAT-directed transgene.
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