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Dissertation
Mitogen induced changes in MAPK signal transduction pathways as a function of age: an exploration in rodent spleen lymphocytes
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Mar 1999
DOI:
https://doi.org/10.17918/00008065
Abstract
It has long been observed that the proliferative capacity of aged lymphocytes decreases with aging. This decreased proliferation correlates with a diminished IL-2 production, which is an important growth factor not only for T cells, but also for B cells. Several signaling pathways, including Ca²⁺/PKC and MAPK, are activated upon T or B cell receptor ligation. Specifically, MAPK pathways are known to be critical for the proliferation of both T and B cells. The objective of my thesis project is to understand the molecular mechanisms underlying the decreased IL-2 production and lymphocyte proliferation observed with aging. As our main approach, we have specifically explored the effect of age on the activation of two MAPK pathways of signal transduction, the ERK and JNK pathways. Limited studies in the literature suggest the existence of some early signaling defects with age in T lymphocytes activated via the TCR/CD3 complex. These early events can be circumvented through the use of PMA plus CaI, which lead to a rise in intracellular free calcium and activation of PKC, respectively. It has been shown that the age-related defect in both T and B cell proliferation is still apparent when cells are stimulated by PMA plus CaI, suggesting the existence of other defects located downstream of the early events. We hypothesise that at least some of these further defects are still located within the signal transduction cascades, but further downstream than previously described. As a model, we have used both rat and mouse splenic lymphocytes, which were stimulated with PMA plus A23187. Thus, our focus was mainly on events that occur downstream of receptor-proximal events. Our results confirm our hypothesis that splenic lymphocytes from old rats and mice have disturbances in both the ERK and JNK signal transduction pathways, which are evident even when the receptor-proximal defects are bypassed. Furthermore, we have identified defects in MEK activation, as well as downstream of the ERK and JNK kinases, at the level of the transcription factors c-Jun and ATF-2. Further studies conducted in purified T- or B-cell-depleted lymphocytes from young animals indicate that there is no difference in their capacity to respond to PMA plus CaI induction. Based on these results, we predict that the defects in MAP kinase activity we have observed in mixed lymphocytes affect both T and B cells. However, extrapolation of data from the literature also allows us to predict that the T cell compartment is likely to be more affected than B cells, because function of the B cell compartment is only marginally affected by aging. The decrease in MAPK activation during aging is likely to play a significant role in the diminished lymphoproliferation observed in older individuals.
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Details
- Title
- Mitogen induced changes in MAPK signal transduction pathways as a function of age
- Creators
- Min Li
- Contributors
- Felipe Sierra (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 169 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888827804721