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Grant Abstract

Grant Number: 5R01AG009140-12
PI Name: MEYDANI, SIMIN N.
Project Title: Aging Vitamin E, and Immune Function in Aged

Abstract: DESCRIPTION (provided by applicant): Aging is associated with a decline in T cell mediated functions, which contributes to a higher incidence of, and morbidity and mortality from, infectious diseases and tumors. The age-related defect in T cells has been shown to be due to intrinsic declines in T cell function, as well as increased production of prostaglandin (PG)E2, a T cell suppressive factor, by macrophages (Mphi). We demonstrated that the increased PGE2 production was due to ceramide mediated upregulation of cyclooxygenase 2 (COX-2) transcription, a key regulatory enzyme in PGE2 synthesis. The signaling mechanism through which ceramide upregulates COX 2 expression, however, is not known and needs to be investigated. We further showed that vitamin E (E) supplementation improves T cell mediated function by two distinct mechanisms: a) by decreasing PGE2 production, thus reducing macrophage Mphi mediated suppression, and b) by directly enhancing T cell function, independent of its effect on Mphi PGE2 production. E exerts its effect by improving the ability of naive T cells from old mice to produce IL-2 and progress through cell division cycles. The mechanism of E-induced enhancement of naive T cell function is not known and needs to be determined. Thus, the specific aims of this proposal are: 1) To determine the signaling pathway involved in ceramide-induced upregulation of COX-2 expression in old Mphi. To accomplish this goal, we will test the hypothesis that ceramide upregulates COX-2 expression in old macrophages through enhancing PKC-zeta activity, leading to increased IkappaB phosphorylation, and thus degradation. This in turn will increase NFkappaB activation and COX-2 expression. 2) To determine the mechanism of E-induced increase in the function of old naive T cells. To accomplish this goal, we will test the hypothesis that E enhances naive T cell function in old mice by increasing their ability to form an effective immune synapse at the site of T cell receptor (TCR) and antigen contact. This, in turn, will lead to improved TCR-associated signal transduction, and subsequent, IL-2 production in old mice. We propose that E induces its effect by changing the redistribution of key TCR associated signaling molecules in membrane lipid domains, known as lipid rafts, by one or both of the following mechanisms: a) increasing palmitoylation of key signaling molecules associated with TCR-mediated activation, and b) changing the structure of the lipid component of lipid rafts. These experiments will elucidate the mechanism of the age-related dysregulation of macrophages and T cells, as well as their normalization by E. This, in turn, will help in designing practical nutritional interventions to reverse and/or delay the age-associated dysregulation of immune and inflammatory responses as well as diseases associated with it.

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