Nicotine, nicotinic receptors and lung cancer

尼古丁、烟碱受体与肺癌

• 批准号: 8815091
• 负责人: ELIOT R SPINDEL
• 金额: $ 42.32万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815091
• 关键词: A/J Mouse; Acetylcholine; Adenocarcinoma; Adenocarcinoma Cell; Affect; Alleles; Amino Acids; Attention; Binding; Calcium; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cell Line; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Cigarette; Code; Data; Development; Electrophysiology (science); Event; Gated Ion Channel; Gene Cluster; Genetic Polymorphism; Genotype; Growth; Growth and Development function; Health; In Vitro; Ion Channel; Knock-in Mouse; Laboratories; Lentivirus Vector; Ligands; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mutate; Mutation; Neuroglia; Neurotransmitter Receptor; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Non-Small-Cell Lung Carcinoma; Nude Mice; Oregon; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Primates; Receptor Gene; Receptor Signaling; Research; Risk; Role; Seminal; Smoke; Smoker; Smoking; Squamous Cell Lung Carcinoma; Stimulus; Testing; Tobacco smoke; Transgenic Mice; United States; cancer cell; cancer risk; cell type; cigarette smoking; genome wide association study; in vivo; interest; knock-down; lung small cell carcinoma; mutant; novel therapeutic intervention; receptor; receptor binding; receptor expression; response; tumor; tumor growth

DESCRIPTION (provided by applicant): The overwhelming majority of lung cancers are associated with smoking and most lung cancers express nicotinic acetylcholine receptors (nAChR) that are activated by the nicotine in cigarette smoke. The objective of this application is to characterize how the interaction of nicotine with nicotinic acetylcholine receptors (nAChR) expressed by lung cancers stimulates tumor growth with the ultimate objective of developing new therapeutic approaches to lung cancer by blocking this proliferative pathway. The nicotinic receptors are ligand-gated ion channels composed of 5 subunits, either a mixture of a and ¿ subunits or 5 of the same a subunit. Binding of a nicotinic agonist such as acetylcholine or nicotine opens the ion channel allowing entry of Na+ or Ca++ into the cell. While the nAChR are best known for their role as neurotransmitter receptors in the CNS, they are also widely expressed in non-neuronal cells. Our laboratory has been a leader in showing that essentially all lung cancers express nAChR and binding of nicotine to the nAChR stimulates lung cancer growth. The real world importance of nicotine as a stimulus for lung cancer growth has recently been confirmed by multiple genome-wide association studies linking polymorphisms in nicotinic receptors to increased risk of lung cancer even when corrected for numbers of cigarettes smoked. Strongest linkage by far has been with polymorphisms in the 15q25.1 nicotinic receptor gene cluster that encodes thea3, a5 and ¿4 nAChR subunits. Critically, the exact role of these nAChR subunits in mediating the ability of nicotine to stimulate cancer growth is unknown. In addition, how the polymorphism of greatest interest, rs16969968 which changes the Asp at residue 398 (a5D398) of the 15 nAChR subunit to Asn (a5N398) affects lung cancer growth is totally unknown. It is also likely that besides the a5D398 to a5N398 mutation, other mutations occur in the 15q25.1 nAChR gene locus that affects lung cancer growth. Therefore, we propose the following 3 specific aims: 1, To determine which nicotinic receptor subtypes in the a3, a5 and ¿4 nAChR gene locus are required for nicotine to stimulate lung cancer growth; 2, To determine the role of the a5D398 to a5N398 mutation (rs16969968) in mediating increased growth and development of lung cancer; and 3, To determine if there are additional common polymorphisms in the a3, a5 and ¿4 nAChR subunits that may increase lung cancer responses to nicotine. Because non-small cell lung cancer (NSCLC) is much more frequent than small cell lung carcinoma (SCLC) we will focus on NSCLC and specifically on squamous cell lung carcinoma (SCC) and lung adenocarcinoma (AC) which are the most frequent forms of NSCLC. These aims will be accomplished using a mix of cell biology, electrophysiology and in vivo studies in nude and transgenic mice to characterize actions of the nAChR receptors in lung cancer. From these studies will come understanding of which nAChR receptors mediate the effects of nicotine on lung cancer growth and thus identify which nAChR and proliferative pathways can be effectively targeted to develop new therapeutic approaches for lung cancer.

描述（由申请人提供）：绝大多数肺癌与吸烟有关，并且大多数肺癌表达被香烟烟雾中的尼古丁激活的烟碱乙酰胆碱受体（nAChR）。本申请的目的是描述烟碱乙酰胆碱受体（nAChR）如何相互作用。肺癌表达的尼古丁和烟碱乙酰胆碱受体（nAChR）可刺激肿瘤生长，最终目标是通过阻断来开发新的肺癌治疗方法烟碱受体是由 5 个亚基组成的配体门控离子通道，可以是 a 和 ¿乙酰胆碱或尼古丁等烟碱激动剂的结合可打开离子通道，允许 Na+ 或 Ca++ 进入细胞，而 nAChR 因其在中枢神经系统中作为神经递质受体的作用而闻名。我们的实验室在表明基本上所有肺癌都表达 nAChR 以及尼古丁与尼古丁的结合方面处于领先地位。 nAChR 刺激肺癌生长。最近多项全基因组关联研究证实了尼古丁作为肺癌生长刺激物的重要性，这些研究将烟碱受体的多态性与肺癌风险增加联系起来，即使根据吸烟数量进行了校正。迄今为止最强的联系是编码 thea3、a5 和 ¿ 的 15q25.1 烟碱受体基因簇中的多态性重要的是，这些 nAChR 亚基在介导尼古丁刺激癌症生长的能力中的确切作用尚不清楚。此外，最令人感兴趣的多态性 rs16969968 如何改变 15 个残基 398 (a5D398) 的 Asp。 Asn (a5N398) 的 nAChR 亚基对肺癌生长的影响也完全未知。除了a5D398到a5N398突变外，15q25.1 nAChR基因位点还发生其他影响肺癌生长的突变，因此，我们提出以下3个具体目标： 1、确定a3、a5和¿中的烟碱受体亚型。 4 nAChR 基因位点是尼古丁刺激肺癌生长所必需的；2，确定 a5D398 至 a5N398 突变 (rs16969968) 在介导肺癌生长和发展中的作用；以及 3，确定是否存在其他常见多态性；在 a3、a5 和 ¿ 4 nAChR 亚基可能会增加肺癌对尼古丁的反应 由于非小细胞肺癌 (NSCLC) 比小细胞肺癌 (SCLC) 更常见，因此我们将重点关注 NSCLC，特别是鳞状细胞肺癌 (SCC) 和肺癌。肺腺癌（AC）是最常见的非小细胞肺癌（NSCLC），这些目标将通过细胞生物学、电生理学和裸鼠和转基因小鼠体内研究的结合来实现，以表征肺腺癌的作用。肺癌中的 nAChR 受体。通过这些研究，我们将了解哪些 nAChR 受体介导尼古丁对肺癌生长的影响，从而确定哪些 nAChR 和增殖途径可以有效地针对肺癌开发新的治疗方法。