Inhibition of chloride secretion by cigarette smoke

香烟烟雾抑制氯离子分泌

• 批准号: 7135940
• 负责人: JAMES Levin KREINDLER
• 金额: $ 12.62万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135940
• 关键词: bronchus; cell line; chloride channels; chloride ion; cilium /flagellum motility; clinical research; cyclic AMP; fluorescence microscopy; ion transport; membrane transport proteins; mucus; oxidation reduction reaction; passive smoking; potassium; proteomics; radiotracer; respiratory airway clearance; respiratory epithelium; smoking; sodium; tobacco abuse

DESCRIPTION (provided by applicant): This proposal describes a 5-year, comprehensive training program designed to provide Dr. Kreindler with the education and mentorship necessary to launch a successful career in academic medicine. Dr. Kreindler completed his postdoctoral fellowship in Pediatric Pulmonology, and is a full-time Assistant Professor of Pediatrics in the Division of Pediatric Pulmonology. His long-term goal is to become an independently-funded clinician scientist with an expertise in the cell biology and physiology of the lung. Accordingly, he will complete formal didactic work in cell biology and physiology, biostatistics, and research design; will have a broad-based experience in the laboratory with exposure to electrophysiology, protein biochemistry, molecular biology, and fluorescence microscopy. Dr. Raymond Frizzell, an internationally recognized expert in cell biology and physiology will serve as Dr. Kreindler's primary sponsor and mentor. Exposure to cigarette smoke causes clinically significant lung disease. Notably, the negative effects of cigarette smoking are not confined to smokers, but extend to those exposed to environmental tobacco smoke. These are often children who are unwillingly exposed and have little opportunity for avoidance. Cigarette smoke is known to damage cilia, increase mucus production, and alter inflammation, such that a cigarette smoke exposed epithelium would need to increase fluid secretion to maintain homeostasis with respect to mucociliary clearance. However, data from our lab and others has shown that cigarette smoke inhibits chloride secretion by airway epithelia, further contributing to the problem of impaired mucociliary clearance. The mechanisms by which this inhibition take place remain incompletely characterized. The hypothesis of this proposal states that cigarette smoke inhibits chloride secretion via oxidation-dependent inhibition of the cAMP-dependent apical anion conductance and inhibits the sodium, potassium, chloride cotransporter. The proposed studies utilize basic and advanced electrophysiology techniques, fluorescence microscopy, and protein biochemical techniques to study the effect of cigarette smoke on ion transport of human bronchial epithelial cells. Changes in chloride secretion will be correlated with changes in airway surface liquid height and mucociliary clearance with the hypothesis that decreases in chloride secretion will correlate with decreased periciliary fluid height and decreased mucociliary clearance. (End of Abstract)

描述（由申请人提供）： 该提案描述了一项为期5年的全面培训计划，旨在为克雷德勒博士提供成功的教育和指导，以开展成功的学术医学职业。 Kreindler博士完成了他在儿科肺病学的博士后奖学金，并且是儿科肺病学科儿科的专职助理教授。他的长期目标是成为一名拥有独立资助的临床医生，在肺部细胞生物学和生理学方面具有专业知识。因此，他将完成细胞生物学和生理学，生物统计学和研究设计方面的正式教学工作。将在实验室中具有广泛的经验，并暴露于电生理学，蛋白质生物化学，分子生物学和荧光显微镜。国际认可的细胞生物学和生理学专家Raymond Frizzell博士将担任Kreindler博士的主要赞助商和导师。暴露于香烟烟雾会引起临床意义的肺部疾病。值得注意的是，吸烟的负面影响不仅限于吸烟者，而是扩展到暴露于环境烟草烟雾的人。这些通常是不愿暴露的孩子，几乎没有避免的机会。众所周知，香烟烟雾会损害纤毛，增加粘液产生并改变炎症，使得香烟烟雾暴露的上皮需要增加液体分泌，以维持有关粘膜切除率的稳态。但是，我们实验室和其他人的数据表明，香烟烟雾会抑制气道上皮的氯化物分泌，进一步导致了粘膜纤毛清除率受损的问题。这种抑制作用的机制仍然不完全表征。该提案的假设指出，香烟烟雾通过氧化依赖性抑制营地依赖性顶端阴离子电导抑制氯化物的分泌，并抑制钠，钾，氯化物cotransporter。拟议的研究利用基本和先进的电生理技术，荧光显微镜和蛋白质生化技术来研究香烟烟雾对人支气管上皮细胞离子转运的影响。氯化物分泌的变化将与气道表面液体高度的变化和粘膜钙清除率与氯化物分泌降低的假设相关，将与周可周围的液体高度降低和粘膜切除率降低相关。 （抽象的结尾）