Remodeling of the airway smooth muscle cell

描述(申请人提供)：急性呼吸道狭窄的末端效应是气道平滑肌(ASM)细胞。ASM细胞有一个处于持续重塑状态的细胞骨架，这种重塑现在被认为是导致哮喘的一个基本特征--气道过度狭窄的主要因素。为了解释这种重塑的程度和进展速度，我们在这里提出了一个新的机制假说。CSK重塑的速度变化很大；根据情况的不同，在同一块肌肉中，重塑可以在短至几天、几小时甚至几分钟的时间内完成。我们在最近的出版物中提出，平滑肌重塑的程度、进展的速度以及驱动它的机制，似乎都符合分子捕获深能井和分子跳出那些由有效基质温度驱动的深能井的框架。这个框架简单、有吸引力，符合所有已发表的观察结果；例如，下面的面板在组织水平上说明，当基质更热时(即，更高的x)，ASM条带确实进行了更多和更快的重建。但支持这一框架及其合理性的论点完全是事后提出的；支持这一框架的证据无一例外都是间接和相关的。这项研究旨在为支持或驳斥这一框架的可行性提供机制基础。该假说预测存在：从一个亚稳态到另一个亚稳态的间歇性纳米尺度跳跃转变；CSK进化到更稳定的微构型的极其缓慢的进化(物理老化)；通过施加足够大的机械应力来重置这种进化，以克服能量障碍并将系统带入新的微构型(恢复活力)。目的1侧重于细胞水平；它旨在测试细胞在生理机械负荷下是否存在衰老和恢复活力。目标2侧重于分子水平；它旨在测试分子规模跃点的存在，并表征驱动这些跃点的分子作用力。目标3整合了这些层次；它旨在将老化、恢复活力和跳跃联系在一起；它建议建立那些老化和恢复活力的结构与通过跳跃重塑的结构是完全相同的。综述：细胞重新排列其内部骨架分子的能力在哮喘的呼吸道狭窄、血管疾病的血管狭窄和癌症的细胞侵袭中起着重要作用。在这里，我们研究一种不同的方式来理解这种基本的重排过程可能是如何工作的。

DESCRIPTION (provided by applicant): The end-effector of acute airway narrowing is the airway smooth muscle (ASM) cell. The ASM cell has a cytoskeleton that is in a continuous state of remodeling, and this remodeling is now thought to be a major factor contributing to the excessive airway narrowing that is a cardinal feature of asthma. To explain the extent of this remodeling and its rate of progression, here we offer a novel mechanistic hypothesis. CSK remodeling proceeds at a rate that varies dramatically; depending upon circumstances, in the same muscle it can be completed on time scales as short as days, hours, or even minutes. We have argued in recent publications that the extent of smooth muscle remodeling, the rate at which it progresses, and the mechanisms that drive it, all appear to fit within the framework of molecular trapping in deep energy wells and molecular hopping out of those wells driven by an effective matrix temperature. This framework is simple, attractive, and fits all published observations; for example, the panels below illustrate at the tissue level that the ASM strip does indeed remodel more and remodel faster while the matrix is "hotter" (i.e., higher x). But the arguments in favor of this framework and its plausibility have been entirely post hoc; without exception the supporting evidence has been circumstantial and correlative. This research is designed to provide the mechanistic basis that would support or refute the tenability of that framework. The hypothesis predicts the existence of: intermittent nano-scale hopping transitions from one metastable state to another; extremely slowly evolution of the CSK into more stable microconfigurations (physical aging); resetting of that evolution by imposed mechanical stresses that are large enough to overcome energy barriers and bring the system to a new microconfiguration (rejuvenation). Aim 1 focuses on the cellular level; it is designed to test the existence of aging and rejuvenation in cells subjected to physiological mechanical loading. Aim 2 focuses on the molecular level; it is designed to test the existence of molecular- scale hops and to characterize the molecular forces that drive those hops. Aim 3 integrates these levels; it is designed to link together aging, rejuvenation, and hopping; it proposes to establish that those structures that age and rejuvenate are the very same ones that remodel by hopping. Lay summary: The ability of the cell to rearrange the molecules of its internal skeleton plays an important role in airway narrowing in asthma, vessel narrowing in vascular disease, and cell invasion in cancer. Here we investigate a different way of understanding how this basic rearrangement process might work.