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（由申请方提供）：长期目的：确定呼吸道细胞中表达的烟碱乙酰胆碱受体（nAChR）对介导烟碱衍生亚硝胺致癌作用的贡献，并鉴定烟草相关致癌作用的解毒剂。基本原理：尼古丁、4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和N '-亚硝基去甲烟碱（NNN）可特异性结合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，凋亡和锚定非依赖性生长的影响。工作假设：nAChR的功能性失活可以：1）在肺肿瘤发生的体外和体内模型中消除NNK和NNN的致癌作用;和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）肺nAChR在人支气管上皮BEP 2D细胞和A/J小鼠培养物中介导NNK和NNN致癌作用中的作用;和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改变。方法学：为了确保特定nAChR亚型与特定致癌物的准确“分配”，我们将使用重叠方法来消除NNK和NNN的影响。我们将确定nAChR选择性药物，小干扰RNA，或反义寡核苷酸，可以消除肿瘤诱导活动的测试亚硝胺。重要性：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。产品描述：拟议的研究阐述了受体介导的烟草致癌物对靶细胞作用的新范式，以及一个充分证实的假设，即前吸烟者肺癌频率增加是由于尼古丁诱导的局部激素乙酰胆碱的肺细胞内结合和信号传导的改变。拟开展的研究将确定每种nAChR亚型在烟草特异性亚硝胺引起呼吸道恶性转化过程中的作用。这些发现将打开一扇大门，为未来的细胞内信号通路介导的致癌和促肿瘤作用的烟草亚硝胺的机制研究。