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）：长期目的：在呼吸细胞中建立烟碱乙酰胆碱受体（NACHR）的贡献，这些受体在呼吸细胞中表达，以介导尼古丁衍生的硝基胺的致癌作用，并鉴定出与与烟草相关的癌变的抗苷酸。基本原理：尼古丁，4-（甲基硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK）和N'-硝基核苷（NNN）可以特异性地与NACHRS结合并改变肺部细胞的生长。我们的初步研究表明，烟碱拮抗剂可以阻止NNK和NNN与肺部细胞的结合，并废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：NACHRS的功能失活可以：1）废除NNK和NNN在体外和体内肺肿瘤模型中的致癌作用； 2）防止胆碱能受体结构和呼吸细胞功能的改变。具体目的：确定：1）肺NACHR的作用在介导NNK和NNN在人支气管上皮BEP2D细胞和A/J小鼠培养中的致癌作用中的作用； 2）胆碱能受体在暴露的呼吸细胞中的基因表达和配体结合能力的改变，小鼠的肿瘤改变了。方法论：确保特定NACHR亚型的准确“分配”对特定的致癌物，我们将使用重叠的方法来废除NNK和NNN的影响。我们将鉴定NACHR选择性药物，小型干扰RNA或反义寡核苷酸，可以消除硝基胺的肿瘤诱导活性。意义：结果将提供至关重要的信息，以确定未来研究的重点阐明特定NACHR亚型在与烟草相关的癌变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的作用的新型范式，以及一个良好的实验性假设，即以前吸烟者中肺癌的频率的增加是尼古丁诱导的与局部激素乙酰胆碱肺肺肺细胞结合和信号传导的变化所致。拟议的研究将确定每个NACHR亚型在响应烟草特异性亚硝基胺的呼吸道转化过程中所涉及的作用。这些发现将为未来的机械研究打开一扇门，以介导烟草硝基胺的致癌作用和肿瘤作用的细胞内信号通路。