Smooth Muscle Mechanisms in Dynamic Airways Properties

潮式呼吸和深吸气引起的气道伸展在正常气道反应性的调节中起重要作用。 拉伸对气道平滑肌张力的影响是由肌肉的机械特性引起的，这些机械特性不能用平滑肌收缩的传统滑动细丝模型来解释：气道肌肉的收缩反应对于任何特定的刺激条件都不是固定的;肌肉适应其收缩行为以响应其机械环境。 提出了一种新的模型，气道平滑肌收缩，可以占这些机械性能，其中主动张力的产生需要两个平行的过程：激活收缩蛋白导致crossbridge循环，和主动重塑和锚定的肌动蛋白丝的膜的力从收缩装置的细胞外基质的传输。 机械应变被提出来调节细胞骨架组织，从而改变收缩器的组织。 有人提出，跨膜整合素感测机械应变，并启动信号级联，触发重组的细胞骨架结构通过肌动蛋白丝重塑和调制其网站的膜附着。 目前项目的重点是确定机械刺激被转导和传递到平滑肌细胞骨架的机制，以及这些信号通路对收缩蛋白激活和细胞骨架结构的影响。 实验将在体外使用气管肌条进行，其中细胞骨架机制在针对细胞骨架蛋白的特定分子相互作用的干预后进行评估。 具体目标是：（1）。评估气道平滑肌收缩器和细胞外基质之间张力传递的分子机制。 2.）评价信号分子黏着斑激酶和桩蛋白在调节气管平滑肌组织收缩蛋白激活和细胞骨架组织的途径中的作用。 3.）第三章评估有助于气管平滑肌收缩功能机械敏感性调节的分子机制。 这些研究将为重要的新信号通路和平滑肌收缩调节的新机制提供证据。 这些概念提供了一个框架，了解如何收缩和功能特性的气道平滑肌调节下发生在呼吸过程中的动态条件。

Stretch of the airways caused by tidal breathing and deep inspiration plays an important role in the regulation of normal airway responsiveness. The effects of stretch on airway smooth muscle tone result from mechanical properties of the muscle that are not explained by traditional sliding filament models of smooth muscle contraction: The contractile responses of airway muscle are not fixed for any particular set of stimulation conditions; the muscle adapts its contractile behavior in response to its mechanical environment. A novel model for airway smooth muscle contraction that can account for these mechanical properties is proposed in which active tension generation requires two parallel processes: the activation of contractile proteins leading to crossbridge cycling, and the active remodeling and anchoring of actin filaments to the membrane for the transmission of force from the contractile apparatus to the extracellular matrix. Mechanical strain is proposed to modulate cytoskeletal organization, thereby changing the organization of the contractile apparatus. It is proposed that transmembrane integrins sense mechanical strain and initiate signaling cascades that trigger the reorganization of cytoskeletal structure via actin filament remodeling and the modulation of their sites of membrane attachment. The focus of the current project is to determine the mechanisms by which mechanical stimuli are transduced and transmitted to the smooth muscle cytoskeleton, and the effect of these signaling pathways on contractile protein activation and cytoskeletal structure. Experiments will be performed using trachealis muscle strips in vitro, in which cytoskeletal mechanisms are ecaluated following interventions that target the specific molecular interactions of cytoskeletal proteins. The specific aims of proposal are: 1.) Evaluate the molecular mechanisms for the transmission of tension between the contractile apparatus and the extracellular matrix in airway smooth muscle. 2.) Evaluate the roles of the signaling molecules focal adhesion kinase and paxillin in pathways regulating the activation of contractile proteins and cytoskeletal organization in tracheal smooth muscle tissues. 3.) Evaluate molecular mechanisms that contribute to the mechanosensitive regulation of contractile function in tracheal smooth muscle. These studies will provide evidence for important new signaling pathways and novel mechanisms for the regulation of smooth muscle contractility. These concepts provide a framework for understanding how the contractility and functional properties of airway smooth muscle are regulated under dynamic conditions that occur during breathing.