Remodeling of the airway smooth muscle cell

描述（由申请人提供）：急性气道狭窄的末端效应器是气道平滑肌（ASM）细胞。ASM细胞具有处于持续重塑状态的细胞骨架，并且这种重塑现在被认为是导致过度气道狭窄的主要因素，过度气道狭窄是哮喘的主要特征。为了解释这种重塑的程度及其进展速度，我们在这里提供了一个新的机制假说。CSK重塑的速度变化很大;根据情况，在同一块肌肉中，它可以在短至几天、几小时甚至几分钟的时间内完成。我们在最近的出版物中指出，平滑肌重塑的程度、进展速度和驱动机制似乎都符合深部能量威尔斯阱中的分子捕获和有效基质温度驱动的分子跳出这些威尔斯阱的框架。该框架简单、有吸引力，并且适合所有已发表的观察结果;例如，下面的图在组织水平上说明，当基质“更热”（即，更高的x）。但是，支持这一框架及其可行性的论点完全是事后的;无一例外，支持证据都是间接的和相关的。本研究旨在提供支持或反驳该框架的可行性的机制基础。该假说预测存在：间歇性纳米级跳跃过渡从一个亚稳态到另一个;非常缓慢的演变CSK到更稳定的微观配置（物理老化）;重置的演变施加的机械应力是足够大，以克服能量障碍，使系统到一个新的微观配置（复兴）。目的1侧重于细胞水平;它旨在测试在生理机械负荷下细胞是否存在老化和再生。目标2集中在分子水平上;它被设计来测试分子尺度啤酒花的存在，并描述驱动这些啤酒花的分子力。目标3整合了这些层面;它旨在将衰老、年轻化和跳跃联系在一起;它建议建立那些衰老和年轻化的结构是通过跳跃重塑的结构。敷设总结：细胞重新排列其内部骨架分子的能力在哮喘的气道狭窄、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，我们研究了一种不同的方式来理解这个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.