Nicotinic receptor-mediated action of tobacco nitrosamines on respiratory cells

烟碱受体介导的烟草亚硝胺对呼吸细胞的作用

• 批准号: 7145522
• 负责人: SERGEI A GRANDO
• 金额: $ 26.53万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-11 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145522
• 关键词: acetylcholine; athymic mouse; biological signal transduction; cancer risk; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; environmental exposure; immunofluorescence technique; laboratory mouse; lung neoplasms; neoplasm /cancer epidemiology; neoplastic transformation; nicotinic receptors; nitrosamines; protein structure function; receptor binding; receptor expression; respiratory epithelium; smoking cessation; tobacco abuse

DESCRIPTION (provided by applicant): Long-term Objective: To establish contribution of nicotinic acetylcholine receptors (nAChRs) expressed in respiratory cells to mediating the oncogenic action of the nicotine-derived nitrosamines and identify antidotes to the tobacco-related carcinogenesis. Rationale: Nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) can specifically bind to nAChRs and alter growth of pulmonary cells. Our preliminary studies indicate that nicotinic antagonists can block binding of NNK and NNN to pulmonary cells and abolish effects of these nitrosamines on cell proliferation, apoptosis and anchorage-independent growth. Working Hypotheses: functional inactivation of nAChRs can: 1) abolish the oncogenic effects of NNK and NNN in in vitro and in vivo models of lung tumorigenesis; and 2) prevent alterations in the cholinergic receptor structure and function in respiratory cells. Specific Aims: to determine: 1) the roles for lung nAChRs in mediating oncogenic effects of NNK and NNN in cultures of human bronchial epithelial BEP2D cells and A/J mice; and 2) alterations in the gene expression and ligand-binding abilities of cholinergic receptors in the exposed respiratory cells, and tumors in mice. Methodology: To assure accurate "assignment" of the specific nAChR subtypes to a particular carcinogen, we will use overlapping approaches to abolish the effects of NNK and NNN. We will identify the nAChR- selective drug, small interfering RNA, or antisense oligonucleotides, that can abolish tumor-inducing activities of test nitrosamines. Significance: The results will provide crucial information for identifying the focus of future research toward elucidation of the role of specific nAChR subtypes in tobacco-related carcinogenesis and lung cancer chemoprevention. Description: The proposed research elaborates a novel paradigm of receptor-mediated action of tobacco carcinogens on target cells, and a well-substantiated hypothesis that an increased frequency of lung cancer in former smokers results from nicotine-induced alterations of binding to and signaling within the lung cells of the local hormone acetylcholine. The proposed studies will establish the role for each nAChR subtype involved in the process of malignant transformation of respiratory in response to the tobacco-specific nitrosamines. These findings will open a door for future mechanistic studies of the intracellular signaling pathways mediating the carcinogenic and tumor-promoting actions of tobacco nitrosamines.

描述（由申请人提供）： 长期目标：确定呼吸细胞中表达的烟碱乙酰胆碱受体（nAChR）对介导尼古丁衍生亚硝胺的致癌作用的贡献，并确定与烟草相关的致癌作用的解毒剂。原理：尼古丁、4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 和 N'-亚硝基降烟碱 (NNN) 可以特异性结合 nAChR 并改变肺细胞的生长。我们的初步研究表明，烟碱拮抗剂可以阻断 NNK 和 NNN 与肺细胞的结合，并消除这些亚硝胺对细胞增殖、凋亡和贴壁依赖性生长的影响。工作假设：nAChR 的功能性失活可以：1）消除 NNK 和 NNN 在肺肿瘤发生的体外和体内模型中的致癌作用； 2) 防止呼吸细胞中胆碱能受体结构和功能的改变。具体目标： 确定： 1) 在人支气管上皮 BEP2D 细胞和 A/J 小鼠培养物中，肺 nAChR 在介导 NNK 和 NNN 致癌作用中的作用； 2）暴露的呼吸细胞和小鼠肿瘤中胆碱能受体的基因表达和配体结合能力的变化。方法：为了确保将特定 nAChR 亚型准确“分配”到特定致癌物，我们将使用重叠方法来消除 NNK 和 NNN 的影响。我们将鉴定 nAChR 选择性药物、小干扰 RNA 或反义寡核苷酸，它们可以消除测试亚硝胺的肿瘤诱导活性。意义：这些结果将为确定未来研究的重点提供重要信息，以阐明特定 nAChR 亚型在烟草相关致癌和肺癌化学预防中的作用。描述：拟议的研究阐述了烟草致癌物对靶细胞的受体介导作用的新范式，以及一个经过充分证实的假设，即戒烟者中肺癌发病率增加是由于尼古丁诱导的与靶细胞内的结合和信号传导的改变所致。肺细胞的局部激素乙酰胆碱。拟议的研究将确定每种 nAChR 亚型在响应烟草特异性亚硝胺的呼吸道恶性转化过程中的作用。这些发现将为未来介导烟草亚硝胺致癌和促肿瘤作用的细胞内信号通路的机制研究打开一扇大门。