ACETYLCHOLINE AND NICOTINIC RECEPTORS IN LUNG CANCER

肺癌中的乙酰胆碱和烟碱受体

• 批准号: 8357740
• 负责人: ELIOT R SPINDEL
• 金额: $ 5.82万
• 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: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357740
• 关键词: Acetylcholine; Calcium; Carcinoma; Cholinergic Antagonists; Epithelial Cells; Funding; Grant; Growth; Growth and Development function; Laboratories; Ligands; Lung; Malignant neoplasm of lung; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; National Center for Research Resources; Neuroendocrine Cell; Nicotine; Nicotinic Receptors; Primates; Principal Investigator; Receptor Activation; Research; Research Infrastructure; Resources; Signal Transduction; Smoking; Source; Squamous cell carcinoma; Type II Epithelial Receptor Cell; United States National Institutes of Health; autocrine; cell growth; cell type; cost; lung small cell carcinoma; novel strategies

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent studies from our laboratory have demonstrated high levels of nicotinic receptors (nAChR) and muscarinic receptors (mAChR) in airway epithelial cells, pulmonary neuroendocrine cells (PNEC) and pulmonary type II cells. Since these cell types are related to the origin of squamous cell carcinomas (SCC), small cell lung carcinomas (SCLC), bronchoalveolar carcinomas (BAC), respectively, it is highly likely that these carcinomas will also express nAChR and mAChR. Since activation of these receptors leads to increased intracellular cellular calcium, their activation typically stimulates cellular growth. Adding further significance is the recent observation from our laboratory that these cell types also make acetylcholine, the ligand for both nAChR and mAChR. This suggests an autocrine loop in which lung cancers secrete acetylcholine to stimulate their own growth. While the expression of nicotinic receptors in SCLC has been previously studied and nicotine has been clearly shown to stimulate growth of SCLC, our observation that SCLC may make acetylcholine and hence modulate their own growth is a new and exciting observation. Hence, how exogenous ligand (i.e., nicotine from smoking) then interacts with the growth promoting effects of endogenous ligand (acetylcholine) becomes a very important question. Thus the purpose of this study is to determine if SCLC, SCC and BAC express acetylcholine, nAChR and mAChR and to then determine the potential for antagonists of cholinergic signaling to provide new approaches to blocking the growth and development of lung cancer. Progress in the current year has demonstrated potential utility for M3 muscarinic antagonists to inhibit lung cancer growth.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们实验室最近的研究表明，气道上皮细胞、肺神经内分泌细胞 (PNEC) 和肺 II 型细胞中存在高水平的烟碱受体 (nAChR) 和毒蕈碱受体 (mAChR)。由于这些细胞类型分别与鳞状细胞癌（SCC）、小细胞肺癌（SCLC）、支气管肺泡癌（BAC）的起源相关，因此这些癌症很可能也表达nAChR和mAChR。由于这些受体的激活会导致细胞内钙的增加，因此它们的激活通常会刺激细胞生长。更重要的是，我们实验室最近观察到，这些细胞类型也会产生乙酰胆碱，即 nAChR 和 mAChR 的配体。这表明肺癌存在自分泌循环，分泌乙酰胆碱来刺激自身生长。虽然之前已经研究过 SCLC 中烟碱受体的表达，并且尼古丁已被清楚地证明可以刺激 SCLC 的生长，但我们观察到 SCLC 可能会产生乙酰胆碱，从而调节其自身的生长，这是一个新的、令人兴奋的观察。因此，外源配体（即吸烟产生的尼古丁）如何与内源配体（乙酰胆碱）的生长促进作用相互作用成为一个非常重要的问题。因此，本研究的目的是确定 SCLC、SCC 和 BAC 是否表达乙酰胆碱、nAChR 和 mAChR，然后确定胆碱能信号传导拮抗剂的潜力，以提供阻止肺癌生长和发展的新方法。 今年的进展已经证明了 M3 毒蕈碱拮抗剂在抑制肺癌生长方面的潜在效用。