NICOTINE/NEUROENDOCRINE SIGNALING IN DEVELOPING LUNG

肺发育中的尼古丁/神经内分泌信号传导

• 批准号: 2029539
• 负责人: CAROL W WUENSCHELL
• 金额: $ 11.54万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029539
• 关键词: acetylcholine; biological signal transduction; cell differentiation; cell growth regulation; cytotoxicity; embryo /fetus; gastrin releasing peptide; gene expression; histogenesis; immunocytochemistry; in situ hybridization; laboratory mouse; lung; messenger RNA; molecular cloning; neuroendocrine system; nicotine; nicotinic receptors; organ culture; polymerase chain reaction; pulmonary surfactants; radioimmunoassay; respiratory epithelium

Prenatal exposure to maternal smoking adversely affects the respiratory health of children even in the absence of postanatal passive smoking. Transplacental nicotine exerts developments effects on fetal lung in animals, including lung hypoplasia and hyperplasia of pulmonary neurodendocrine cells. Paradoxically, the lungs of smoking-exposed infants appear to be more mature at birth than those of unexposed infants. The cellular and molecular mechanisms underlying these prenatal effects of maternal smoking are presently unknown. The study will use culture of whole embryonic mouse lungs in chemically defined medium as a model system to study the mechanism of nicotine action in development lung. Preliminary data show stimulation of branching and expression of the genes encoding the peptide growth factor GRP and surfactant proteins SP-C and SP-A in nicotine-treated lungs. The effect on SP-C gene expression is blocked by the nicotinic antagonist d-tubocurarine. Further, the increase in SP-C gene expression is blocked an antibody directed against the reactive region of GRP. Thus, the effects of nicotine in this system are mediated by nicotinic acetycholine receptor (nAChR) subtype and GRP may be a mediator in the downstream pathway. The added observation that embryonic lung distal epithelial cells posses and partial neuroendocrine phenotype leads to his hypothesis; That nicotine alters the developmental program of the embryonic lung including expression of surfactant protein genes, through a mechanism involving nAChRs located on cells of the distal epithelium and stimulation of production of GRP by these name distal epithelial cells. The specific Aims are: 1) To characterize the effects of added nicotine on development of embryonic lung with respect to growth, branching morphogenesis, specific gene expression and differentiation of epithelial cells. 2) To determine the nature and location of the nAChRs mediating the developmental effects of nicotine in embryonic lung. 3) To test the role of GRP as a downstream mediator of nicotine effects by blocking strategies. The results of this study will provide insights into an aspect of normal lung development that has not previously been explored, as well as increasing our understanding of the mechanism of nicotine toxicity in developing lung and possible cancer risks from prenatal nicotine exposure.

产前暴露于母亲吸烟的不利影响 即使没有产后呼吸系统的健康 被动吸烟。 经胎盘尼古丁发挥作用的进展 对动物胎儿肺的影响，包括肺发育不全和 肺神经内分泌细胞增生。 矛盾的是， 暴露于吸烟的婴儿的肺部似乎在 出生率高于未暴露的婴儿。 细胞和分子 母亲吸烟对产前影响的机制 目前未知。 该研究将使用整个文化 化学成分确定的培养基中的胚胎小鼠肺作为模型 研究尼古丁在发育过程中作用机制的系统 肺。 初步数据显示刺激分支和 编码肽生长因子 GRP 的基因的表达 尼古丁处理的肺中的表面活性蛋白 SP-C 和 SP-A。 对 SP-C 基因表达的影响被烟碱阻断 拮抗剂 d-筒箭毒碱。 此外，SP-C基因的增加 表达被针对反应性抗体的阻断 GRP 区域。因此，尼古丁在该系统中的作用是 由烟碱乙酰胆碱受体 (nAChR) 亚型介导 GRP 可能是下游途径的介质。 所添加的 观察到胚胎肺远端上皮细胞具有 部分神经内分泌表型导致了他的假设；那 尼古丁改变胚胎肺的发育程序 包括表面活性剂蛋白基因的表达，通过 涉及位于远端细胞上的 nAChR 的机制 上皮细胞和 GRP 产生的刺激 远端上皮细胞。 具体目标是： 1) 表征 添加尼古丁对胚胎肺发育的影响 关于生长、分枝形态发生、特定基因 上皮细胞的表达和分化。 2）确定 介导发育的 nAChR 的性质和位置 尼古丁对胚胎肺的影响。 3）测试GRP的作用 通过阻断策略作为尼古丁效应的下游调节剂。 这项研究的结果将提供对以下方面的见解： 以前从未探索过的正常肺部发育，如 以及增加我们对尼古丁作用机制的了解 肺部发育中的毒性和产前可能的癌症风险 尼古丁暴露。