There is good evidence that aging is accompanied by changes in the immune system that 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 down stream such as induction and regulation of transcription factors and their impact on immune function during senescence needs 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 fully define 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 factors contributing to immune dysfunction with aging. Plans are to focus attention on a highly inducible and pleiotropic transcription factor NFkB (nuclear factor kappa B). NFkB is an important transcription factor composed of several subunits that in genetic programs that 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-alpha. Preliminary studies demonstrate that aging is accompanied by lowered induction of NFkB. To understand the basis for this age-related alteration plans are to characterize age-related regulatory changes in the induction of NFkB, induction and degradation of IkB and finally, to examine the role of NFkB in age-associated decrease in mitogen-induced IL- 2 transcription. The intent is that results from these studies will provide insights into the role of pleiotropic transcription factor NFkB in T cells and may provide a molecular basis for immune dysfunction in aging human T cells. In addition, these results will form a data base for future studies delineating similar senescent changes in other cell types and provide potential therapeutic strategies for geriatric diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG4-GRM (01))
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University of Arkansas for Medical Sciences
Internal Medicine/Medicine
Schools of Medicine
Little Rock
United States
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Ponnappan, Subramaniam; Ponnappan, Usha (2011) Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal 14:1551-85
Cullen, Sarah J; Ponnappan, Subramaniam; Ponnappan, Usha (2010) Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation. Biochem Pharmacol 79:706-14
Cullen, Sarah J; Ponnappan, Subramaniam; Ponnappan, Usha (2009) Catalytic activity of the proteasome fine-tunes Brg1-mediated chromatin remodeling to regulate the expression of inflammatory genes. Mol Immunol 47:600-5
Sun, Lu; Hodeify, Rawad; Haun, Shirley et al. (2008) Ca2+ homeostasis regulates Xenopus oocyte maturation. Biol Reprod 78:726-35
Das, Rupali; Ponnappan, Subramaniam; Ponnappan, Usha (2007) Redox regulation of the proteasome in T lymphocytes during aging. Free Radic Biol Med 42:541-51
Ponnappan, Subramaniam; Ovaa, Huib; Ponnappan, Usha (2007) Lower expression of catalytic and structural subunits of the proteasome contributes to decreased proteolysis in peripheral blood T lymphocytes during aging. Int J Biochem Cell Biol 39:799-809
Ponnappan, Subramaniam; Cullen, Sarah J; Ponnappan, Usha (2005) Constitutive degradation of IkappaBalpha in human T lymphocytes is mediated by calpain. Immun Ageing 2:15
Ponnappan, Subramaniam; Uken-Trebilcock, Gina; Lindquist, Michael et al. (2004) Tyrosine phosphorylation-dependent activation of NFkappaB is compromised in T cells from the elderly. Exp Gerontol 39:559-66
Ponnappan, Usha (2002) Ubiquitin-proteasome pathway is compromised in CD45RO+ and CD45RA+ T lymphocyte subsets during aging. Exp Gerontol 37:359-67
Ponnappan, U; Soderberg, L S (2001) Inflammatory macrophage nuclear factor-kappaB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite. J Leukoc Biol 69:639-44

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