: Among the deleterious effects associated with the use of tobacco products is the suppression of the immune function. Preliminary data demonstrates that nicotine, and its major metabolite cotinine, inhibit the expression and activity of cyclin-dependent kinase 4 (Cdk4). The inhibition of Cdk4 by nicotine and cotinine presents a potential mechanistic link between tobacco use and immune system dysfunction; the repression of Cdk4 by nicotine and cotinine induces cytokine unresponsiveness leading to immune system tolerance (or anergy). Hypothesis: Nicotine and cotinine exert immunosuppressive effects principally by repressing Cdk4 gene transcription and by altering Ckl interact ions. These actions are transduced through nicotinic acetylcholine receptors, involving calcium signaling, calcineurin and NFATI. This hypothesis will be tested with the following specific aims (1) Determine the extent and the mechanism(s) of the nicotine and cotinine induced repression of Cdk4 expression and competence induction, (2) Define the signaling pathway, cell surface receptor(s), and intervening molecules involved in the nicotine and cotinine induced repression of Cdk4. Both effects at the protein level by immuno-blot, and RNA level by RNase protection, will be explored in primary human T cells, with additional techniques including, receptor antagonist, electrophorectic mobility shift assay and array analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI050392-02
Application #
6626215
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Prograis, Lawrence J
Project Start
2002-05-01
Project End
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$46,420
Indirect Cost
Name
Amc Cancer Research Center
Department
Type
DUNS #
016207271
City
Denver
State
CO
Country
United States
Zip Code
80214
Oloris, Silvia C S; Frazer-Abel, Ashley A; Jubala, Cristan M et al. (2010) Nicotine-mediated signals modulate cell death and survival of T lymphocytes. Toxicol Appl Pharmacol 242:299-309
Frazer-Abel, Ashley A; Baksh, Shairaz; Fosmire, Susan P et al. (2004) Nicotine activates nuclear factor of activated T cells c2 (NFATc2) and prevents cell cycle entry in T cells. J Pharmacol Exp Ther 311:758-69