Ion Transport and Mucus Clearance in CF Airways

CF 航空中的离子传输和粘液清除

• 批准号: 7038269
• 负责人: ROBERT TARRAN
• 金额: $ 21.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038269
• 关键词: actins; adenosine triphosphate; biological signal transduction; chloride ion; clinical research; confocal scanning microscopy; cystic fibrosis; cytoskeleton; fluorescence resonance energy transfer; human tissue; ion transport; mucus; respiratory airway clearance; respiratory airway pressure; respiratory airway volume; saliva; secretion; shear stress; sodium ion

DESCRIPTION (provided by applicant): We have previously shown that the height (volume) of normal (NL) airway surface liquid (ASL) is regulated, but the underlying mechanisms are unknown and the relevance to disease (e.g., cystic fibrosis; CF) controversial. Our long-term goal is to understand how ASL volume is autoregulated in NL and CF airway epithelia under physiological conditions. The specific hypothesis behind the proposed research is that ATP and ADO act as shear stress-dependent signals encoded in the ASL to autoregulate NL and CF ASL volume by modulating ion transport (Na+absorption and CI-secretion). This hypothesis is based on data obtained with a novel system that mimics the shear stress imparted by the lung in vivo during normal tidal breathing. Shear stress induced a realignment of the actin cytoskeleton in the direction of the applied shear, increased ATP release into the airway surface liquid and increased the distance between the 5' ectonucleotidase (the ecto-enzyme responsible for making adenosine on airway surfaces) and the A2b adenosine receptor, as measured by fluorescence resonance energy transfer (FRET). These studies provide a first step towards understanding how shear stress may be sensed and transduced in airway epithelia. We also found that principal effectors were activated by shear stress: extracellular purine nucleotide (ATP)- and nucleoside (adenosine)-dependent pathways for ASL autoregulation were increased in normal airway epithelia while cystic fibrosis airways relied solely on a motion-dependent ATP pathway to rebalance abnormal CF ion transport and adjust ASL height to levels adequate for mucus transport. Based on these observations, the specific aims of this proposal are (1) to identify sensors of ASL volume, (2) to understand how ASL volume regulation is transduced and (3) to normalize CF airway surface liquid volume regulation.

描述（由申请人提供）：我们先前表明，调节正常（NL）气道表面液体（ASL）的高度（体积），但潜在机制是未知的，与疾病（例如囊性纤维化； CF）相关性。我们的长期目标是了解生理条件下NL和CF气道上皮中的ASL体积如何自动调节。拟议的研究背后的特定假设是，ATP和ADO充当ASL中编码的剪切应力依赖性信号，可通过调节离子转运（Na+吸收和CI-分泌）来自动调节NL和CF ASL体积。该假设基于使用新型系统获得的数据，该系统模拟了正常潮汐呼吸期间肺部体内施加的剪切应力。剪切应力诱导肌动蛋白细胞骨架沿施加的剪切方向进行重组，增加了ATP释放到气道表面液体中，并增加了5'Ecton核苷酸酶（负责在气道表面上产生腺苷）和A2B腺苷受体的能量的5'核核苷酸酶之间的距离（肾上腺素酶）的距离（均能通过含量转移）。这些研究提供了了解如何在气道上皮中感测和转导的剪切应力的第一步。我们还发现，主要效应子是通过剪切应力激活的：细胞外嘌呤核苷酸（ATP）和核苷（腺苷）依赖性途径的ASL自动调节途径增加了正常气道上皮elia中的囊性纤维化中的囊性纤维化，而依赖于运动型ATP依赖于ASL的ASL依赖于ASL的ASL依赖于ASL的ASL依赖于ASL的ASL依赖于ASL，并适应了ASL的ASL。基于这些观察结果，该提案的具体目的是（1）识别ASL体积的传感器，（2）了解ASL体积调节是如何转导的，以及（3）使CF Airway表面液体体积调节的正常化。