Calcium signaling in airway smooth muscle in lung slices

肺切片气道平滑肌中的钙信号传导

基本信息

批准号：
7272686
负责人：
MICHAEL J. SANDERSON
金额：
$ 30.15万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A characteristic of asthma is airway hyper-reactivity, a response acutely mediated by smooth muscle cell (SMC) contraction. SMC contractility is initiated by increases in intracellular calcium concentration ([Ca2+]i) but the mechanisms of Ca2+ signaling in airway SMCs and how these relate to changes in airway caliber are poorly understood. To address this problem, we have developed a unique lung slice preparation that retains many properties of the lung structure, and in which the Ca2+ signaling of the SMCs and the associated airway contraction or relaxation can be measured simultaneously with confocal microscopy. Our data shows that airway SMCs display a graded range of IP3-based Ca2+ signaling that consists of elemental Ca2+ signals, intracellular Ca2+ oscillations and Ca2+ waves and that these signals correlate with the establishment of resting airway tone as well as the initiation and maintenance of SMC and airway contraction. Consequently, we hypothesize that the frequency of the Ca2+ signals in SMCs serves to regulate Ca2+ airway caliber. To test this idea, we plan to determine: 1) the Ca signaling mechanisms responsible for the Ca2+ establishment of resting airway tone by investigating the elemental Ca signaling and mechanism of spontaneous Ca2+ oscillations and contractions of airway SMCs, 2) if airway caliber is regulated by frequency-modulation (FM) mediated by Ca2+ oscillations, and 3) how Ca2+ signaling and contraction is altered in airway SMCs of mouse models for hyper-reactivity and asthma. By understanding the graded mechanisms of elemental Ca2+ signaling and Ca2+ oscillations in lung SMCs and how these events regulate SMC contractility and relate to airway caliber, we can gain the necessary insight needed to approach a therapeutic strategy for modulating airway hyper-reactivity.

描述（由申请人提供）：哮喘的一个特征是气道高反应性，这是由平滑肌细胞（SMC）收缩急剧介导的反应。 SMC 收缩性是由细胞内钙浓度 ([Ca2+]i) 的增加引发的，但气道 SMC 中 Ca2+ 信号传导的机制以及这些机制与气道口径变化的关系尚不清楚。为了解决这个问题，我们开发了一种独特的肺切片制剂，它保留了肺结构的许多特性，并且可以用共聚焦显微镜同时测量 SMC 的 Ca2+ 信号传导和相关的气道收缩或舒张。我们的数据显示，气道 SMC 显示一系列基于 IP3 的 Ca2+ 信号传导，包括元素 Ca2+ 信号、细胞内 Ca2+ 振荡和 Ca2+ 波，这些信号与静息气道张力的建立以及 SMC 的启动和维持相关和气道收缩。因此，我们假设 SMC 中 Ca2+ 信号的频率可以调节 Ca2+ 气道口径。为了测试这个想法，我们计划确定：1) 通过研究气道 SMC 的基本 Ca2+ 信号传导和自发 Ca2+ 振荡和收缩的机制，负责 Ca2+ 建立静息气道张力的 Ca2+ 信号传导机制，2) 气道口径是否受到调节通过 Ca2+ 振荡介导的调频 (FM)，以及 3) 在高反应性和哮喘小鼠模型的气道 SMC 中 Ca2+ 信号传导和收缩如何改变。通过了解肺 SMC 中元素 Ca2+ 信号传导和 Ca2+ 振荡的分级机制，以及这些事件如何调节 SMC 收缩性以及与气道口径的关系，我们可以获得必要的见解，以制定调节气道高反应性的治疗策略。