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：
7152926
负责人：
Julian Solway
金额：
$ 36.15万
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/7152926
关键词：
1,2-diacylglycerol Acids Actomyosin Acute Agonist Anisomycin Asthma Attention Behavior Binding Biochemical Biological Models Breathing Bronchoconstriction Bronchodilation Calcium Calcium ion Caliber Candy Canis familiaris Characteristics Complex Contracts Coupled Cytochalasin D Depth Diglycerides Dominant-Negative Mutation Elasticity Elevation Equilibrium Event F-Actin Failure GTP-Binding Proteins Gelsolin Genetic Transduction HSPB1 gene Human Individual Intervention Isotonic Contraction Length Light Lung MAP Kinase Gene MAP2K6 gene MAPK14 gene MAPKAPK2 gene MEKs MYLK gene Measures Mechanics Mediating Microfilaments Mitogen-Activated Protein Kinase Inhibitor Molecular Muscarinic M2 Receptor Muscle Muscle function Myosin Light Chains N-terminal Obstruction Pathway interactions Peptides Phase Phosphorylation Physiological Plasmids Plastics Property Protein Isoforms Protein Overexpression Radial Rain Rate Receptor Activation Regulation Rubber SB 203580 Signal Pathway Signal Transduction Simulate Smooth Muscle Stretching Structure of parenchyma of lung System Testing Time Tissues Traction Tropomyosin Upper arm Waxes asthmatic airway caldesmon caspase-3 design experience inhibitor/antagonist jasplakinolide latrunculin B mutant myosin phosphatase novel novel therapeutics prevent profilin respiratory smooth muscle response stem

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）：虽然气道收缩性过度反应性长期以来一直被称为哮喘的病理生理特征，但最近关注了另一个功能异常 - 在正常人中，深呼吸无法反向哮喘受试者逆转支气管支气管理。哮喘气道似乎以弹性的方式对深呼吸施加的拉伸做出了反应，并在释放深入吸入后不久又回到了原始的，狭窄的直径。在明显的对比度中，正常气道在狭窄的响应时正常的气道以更大的塑性变形响应，保留了伸展的圆周，并导致深呼吸引起的支气管收缩逆转。充分的证据表明，狭窄的气道的塑性或弹性行为起源于其收缩气道平滑肌的平行机械性能。我们的主要目的是确定调节合同气道平滑肌可塑性平衡的分子机制。该提案的基本前提是1）对深层灵感的正常支气管扩张反应是很大的影响，2）这种反应在哮喘中消除了，3）如果我们理解了这种反应及其哮喘失败的分子机制，那么可以将这种新颖的干预措施恢复这种疗法的策略，并且可以自言自语，并且可以自言自语，并且可以自言自语。我们已经开发了一种新型的模型系统，该系统促进了对合同气道平滑肌的可塑性弹性平衡的研究，在我们发现在等渗收缩过程中发生的缩短会因增加负载波动而逆转，并且这种关系加剧在两个时间尺度上发生 - 在几秒钟内（“直接阶段”），以及在整个阶段（“速度较慢”的速度（slotes of of Force osscill）（slow of Osscill）（slow of Ossossoscillation of Oscillation oscillation osscillation osscillation''（''slow oscillation oscillation''（”）其他研究暗示不同的信号通路和不同的效应分子在每个阶段的关系加长的调节中。因此，该模型系统揭示了多种（至少2个）分子机制决定了合同气道平滑肌的总体可塑性，并且为其单独研究提供了一个平台。使用该系统，我们提出了两个特定的目标，旨在识别信号通路和效应分子，这些分子对合同气道平滑肌的整体可塑性进行了两个易于辨别的贡献。我们预计，理解这些分子机制可能会使哮喘中气道平滑肌中这些途径的潜在失调，因此可能建议通过这些策略来恢复强大的内源性保护性深呼吸诱导的支气管降解，从而在哮喘中丧失。