Plasticity Regulation of Contracted Airway Smooth Muscle

收缩气道平滑肌的可塑性调节

基本信息

批准号：
6863341
负责人：
Julian Solway
金额：
$ 33.53万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6863341
关键词：
acetylcholine asthma biological signal transduction bronchomotion calcium flux caldesmon cell surface receptors dogs elasticity human tissue mitogen activated protein kinase muscle contraction neuromuscular transmission protein kinase C pulmonary respiration respiratory muscles smooth muscle

项目摘要

DESCRIPTION (provided by applicant): While airway constrictor hyperresponsiveness has long been known as a pathophysiological characteristic of asthma, more recent attention has been placed upon another functional abnormality - the inability of deep breathing to reverse bronchoconstriction in asthmatic subjects, as it does in normal individuals. Asthmatic airways appear to respond to the stretch imposed by a deep breath in an elastic fashion, returning to their original, constricted diameter soon after release of the deep inhalation. In marked contrast, normal airways when constricted respond to stretch with much more plastic deformation, retaining their stretched circumference and resulting in deep breathing-induced reversal of bronchoconstriction. Ample evidence indicates that plastic or elastic behavior of a constricted airway has its origin in the parallel mechanical properties of its contracted airway smooth muscle. Our major objective is to identify the molecular mechanisms that regulate the plasticity-elasticity balance of contracted airway smooth muscle. The key premises underlying this proposal are that 1) the normal bronchodilation response to a deep inspiration is a large effect, 2) this response is abrogated in asthma, and 3) if we understood the molecular mechanisms underlying this response and its failure in asthma, then novel interventions could be designed to restore this bronchodilation mechanism in asthmatics, and could represent an important new therapeutic strategy. We have developed a novel model system that facilitates study of the plasticity-elasticity balance of contracted airway smooth muscle, which in we find that the shortening that occurred during isotonic contraction is reversed by the addition of load fluctuations, and that this relengthening happens on two time scales - within a few seconds ("immediate phase") and over the entire 20 min of force oscillation ("slow phase"); additional studies implicate different signaling pathways and different effector molecules in the regulation of each phase of relengthening. This model system thus reveals that multiple (at least 2) molecular mechanisms determine overall plasticity of contracted airway smooth muscle, and it provides a platform for their separate study. Using this system, we propose two specific aims designed to identify the signaling pathways and effector molecules that regulate two easily discernible contributions to the overall plasticity of contracted airway smooth muscle. We anticipate that understanding these molecular mechanisms may shed light onto potential dysregulation of these pathways in airway smooth muscle in asthma, and so may suggest strategies by which to restore the powerful endogenous protective deep breath-induced bronchodilation that is lost in asthma.

描述（由申请人提供）：虽然气道收缩过度反应长期以来一直被认为是哮喘的病理生理学特征，但最近人们的注意力集中在另一种功能异常上 - 深呼吸无法逆转哮喘受试者的支气管收缩，就像正常人一样个人。哮喘气道似乎以弹性方式对深呼吸所施加的拉伸做出反应，在深吸气释放后不久就恢复到原来的收缩直径。与此形成鲜明对比的是，正常气道在收缩时会对拉伸做出更大的塑性变形反应，保持其拉伸的周长，并导致深呼吸引起的支气管收缩逆转。充足的证据表明，收缩气道的塑性或弹性行为起源于收缩气道平滑肌的平行机械特性。我们的主要目标是确定调节收缩气道平滑肌塑性-弹性平衡的分子机制。这一提议的关键前提是：1）对深吸气的正常支气管扩张反应有很大影响，2）这种反应在哮喘中被消除，3）如果我们了解这种反应背后的分子机制及其在哮喘中的失败，然后可以设计新的干预措施来恢复哮喘患者的这种支气管扩张机制，并且可以代表一种重要的新治疗策略。我们开发了一种新颖的模型系统，有助于研究收缩气道平滑肌的塑性-弹性平衡，我们发现等张收缩期间发生的缩短通过增加负荷波动而逆转，并且这种重新延长发生在两个时间尺度 - 几秒钟内（“立即阶段”）和整个 20 分钟的力振荡（“慢阶段”）；其他研究表明不同的信号通路和不同的效应分子参与了再延长每个阶段的调节。因此，该模型系统揭示了多种（至少 2 个）分子机制决定了收缩气道平滑肌的整体可塑性，并为他们的单独研究提供了平台。使用该系统，我们提出了两个具体目标，旨在识别信号通路和效应分子，调节对收缩气道平滑肌整体可塑性的两个容易辨别的贡献。我们预计，了解这些分子机制可能会揭示哮喘气道平滑肌中这些途径的潜在失调，因此可能会提出恢复哮喘中失去的强大内源性深呼吸诱导支气管扩张的策略。