Mechanisms of Nicotine Induced Immunosuppression

尼古丁诱导免疫抑制的机制

• 批准号: 6748530
• 负责人: ASHLEY A FRAZER-ABEL
• 金额: $ 2.56万
• 依托单位: AMC CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2004-10-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748530
• 关键词: RNase protection assay; T lymphocyte; artificial immunosuppression; calcineurin; calcium flux; cell surface receptors; clinical research; cyclin dependent kinase; enzyme induction /repression; gel mobility shift assay; human subject; immunogenetics; immunopharmacology; leukocyte activation /transformation; nicotine; nicotinic receptors; pharmacogenetics

DESCRIPTION (provided by the applicant): 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.

描述（由申请人提供）：在有害效果中 与使用烟草产品有关的是免疫的抑制 功能。初步数据表明尼古丁及其主要代谢物 可替宁，抑制细胞周期蛋白依赖性激酶4的表达和活性 （CDK4）。尼古丁和可替宁对CDK4的抑制作用具有潜力 烟草使用与免疫系统功能障碍之间的机械联系；这 尼古丁和可替宁对CDK4的抑制会诱导细胞因子无反应性 导致免疫系统的耐受性（或反感）。假设：尼古丁和 可替宁主要通过抑制CDK4基因发挥免疫抑制作用 转录和通过改变CKL相互作用离子。这些动作被转移 通过烟碱乙酰胆碱受体，涉及钙信号传导， 钙调神经和NFATI。该假设将通过以下测试 具体目的（1）确定尼古丁的程度和机制和机制 可替氨酸诱导CDK4表达和能力诱导的抑制作用，（2） 定义信号通路，细胞表面受体和中间 参与尼古丁和可替宁诱导CDK4的分子。 这两种作用在蛋白质水平上通过免疫印迹和RNase的RNA水平在蛋白质水平上的作用 保护将在原代人T细胞中探索，并附加 技术包括受体拮抗剂，电泳迁移率移动 测定和阵列分析。