This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cigarette smoking is a risk factor for cancer and cardiovascular disease. One mechanism by which smoking contributes to both diseases is via stimulation of chronic inflammation. Chronic inflammation causes up to 25% of all cancers and is the foundation for atherosclerosis. Normally, inflammation is limited, requiring balance between pro- and anti-inflammatory cytokines. A tobacco-induced shift in pro- or anti-inflammatory cytokines could upset this balance and contribute to disease. This proposal will identify effects of smoking on key pro- and anti-inflammatory cytokines and C-reactive protein. In addition, the effect of tobacco on the methylation (silencing) of two genes will be investigated; 1) the gene coding for tumor necrosis factor alpha (TNF-a) and 2) the gene coding for the immune system regulatory protein 'target of methylation-induced silencing' (TMS1/ASC). Two hypotheses will be tested: 1) Smokers will differ in cytokines and CRP compared to non-smokers, which will reverse during smoking abstinence; 2) Smokers will demonstrate increased methylation of genes coding for TNF-a and TMS1/ASC, which will reverse during abstinence. TNF-a and TMS1/ASC are tumor suppressors that activate cell suicide in the presence of mutation. Silencing these genes, may cause mutations induced by tobacco smoke to be passed on during cell division leading to cancer initiation. Smokers and non-smokers will participate in an in-patient study, involving a 1-day baseline and a 6-day period of smoking abstinence. Cytokines, gene methylation and CRP will be measured daily. This research will provide information on inflammation and gene methylation that may explain smoking-related risk and reversibility of risk.
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