There is good evidence that aging is accompanied by changes in the immune system which contribute to the initiation and progression of geriatric diseases. However, the fundamental mechanism underlying immune dysfunction in aging remains to be fully defined. Studies conducted to date have clearly documented age-related defects in early signaling events, but events downstream, such as induction and regulation of transcription factor and their impact on immune senescence, need to be elucidated. The objective of this study is to understand the biochemical basis of immune dysfunction that accompanies aging, by focusing on the role of transcription factor regulation in aging. The long-term goal of this research is to understand the biochemical and molecular mechanism/s underlying immune dysregulation in aging. The working hypothesis is that activation of surface receptors on T-cells from elderly donors, fails to activate appropriate transcription factor, contributing to immune dysfunction associated with aging. The investigator will focus her attention on a highly inducible and pleiotropic transcription factor, NFkB (nuclear factor kappa B). NFkappaB is an important transcription factor, composed of several subunits that participate in genetic programs which mediate T-cell growth and proliferation. Nuclear expression of NFkB occurs following activation, while it is largely cytosolic in resting T-cells. In the cytosol, it is found in association with its inhibitor, IkB. Upon activation, NFkB is released from the inhibitor allowing translocation to the nucleus where it activates the expression of genes like IL-2 and IL-2 receptor. In an attempt to delineate the role of NFkB in aging, the application proposes to identify and characterize age-related changes in the induction of NFkB, induction and degradation of inhibitor IkB and examine the role of NFkB in age-associated decreases in antigen-induced proliferation. The data from these studies are intended to provide insights into the role of the pleiotropic transcription factor NFkB in T-cells and may provide a molecular basis for immune dysfunction in aging in human T-cells. In addition, the data are intended to form a data base for future studies delineating similar senescent changes in other cell types and provide potential therapeutic strategies for geriatric diseases.
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