INFLAMMATION AND INFLAMMATION-RELATED GENE SILENCING IN SMOKERS AND NON-SMOKERS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。吸烟是癌症和心血管疾病的危险因素。吸烟导致这两种疾病的一个机制是通过刺激慢性炎症。慢性炎症导致25%的癌症，是动脉粥样硬化的基础。正常情况下，炎症是有限的，需要促炎性和抗炎性细胞因子之间的平衡。烟草引起的促炎或抗炎细胞因子的变化可能会破坏这种平衡并导致疾病。该提案将确定吸烟对关键促炎和抗炎细胞因子和c反应蛋白的影响。此外，还将研究烟草对两个基因甲基化（沉默）的影响；1)肿瘤坏死因子α (TNF-a)基因编码和2)免疫系统调节蛋白“甲基化诱导沉默靶蛋白”（TMS1/ASC）基因编码。将测试两个假设：1)吸烟者与非吸烟者在细胞因子和CRP方面存在差异，在戒烟期间这种差异将会逆转；2)吸烟者会表现出编码TNF-a和TMS1/ASC的基因甲基化增加，这种情况在戒烟期间会逆转。TNF-a和TMS1/ASC是在突变存在时激活细胞自杀的肿瘤抑制因子。沉默这些基因可能会导致烟草引起的突变在细胞分裂期间传递，从而导致癌症的发生。吸烟者和非吸烟者将参加一项住院研究，包括1天的基线和6天的戒烟期。每天检测细胞因子、基因甲基化和CRP。这项研究将提供炎症和基因甲基化的信息，可能解释吸烟相关的风险和风险的可逆性。

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.