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(申请人提供)：长期目标：确定在呼吸道细胞中表达的尼古丁型乙酰胆碱受体(NAChRs)在介导尼古丁衍生的亚硝胺的致癌作用中的作用，并确定烟草相关致癌的解毒剂。研究原理：尼古丁、烟碱(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone，NNK)和N‘-亚硝基烟碱(N’-NitrosonorNicotine，NNN)可与nAChRs特异性结合，改变肺细胞的生长。我们的初步研究表明，尼古丁拮抗剂可以阻断NNK和NNN与肺细胞的结合，并取消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：nAChRs的功能失活可以：1)在肺肿瘤的体外和体内模型中消除NNK和NNN的致癌作用；2)防止呼吸细胞胆碱能受体结构和功能的改变。具体目的：1)确定肺nAChRs在NNK和NNN对人支气管上皮BEP2D细胞和A/J小鼠培养的致癌作用中的作用；2)暴露于呼吸道细胞和小鼠肿瘤中胆碱能受体基因表达和配体结合能力的变化。方法：为了确保特定的nAChR亚型对特定致癌物的准确“分配”，我们将使用重叠的方法来取消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，可以取消受试者亚硝胺的致癌活性。意义：这些结果将为确定未来研究的重点提供关键信息，以阐明特定的nAChR亚型在烟草相关癌症发生和肺癌化学预防中的作用。描述：这项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例，以及一个得到充分证实的假设，即前吸烟者肺癌发生率的增加是由于尼古丁诱导局部荷尔蒙乙酰胆碱与肺细胞的结合和肺细胞内信号的变化。拟议的研究将确定每个nAChR亚型在烟草特有的亚硝胺引起的呼吸道恶变过程中所起的作用。这些发现将为未来对烟草亚硝胺致癌和促癌作用的细胞内信号通路的机制研究打开大门。