Structure and Function of cell adhesion sites

整合素依赖性粘附和信号传导是细胞运动、存活和对细胞凋亡的反应所必需的。 机械提示呼吸系统、心血管系统、肌肉骨骼系统和泌尿生殖系统的细胞 作为他们正常生理的一部分暴露在身体紧张中。细胞会对机械的 通过重塑肌动蛋白细胞骨架和采用新的基因表达程序来应对压力。尽管 机械信号对胚胎发育、伤口愈合和组织 然而，关于物理力如何影响细胞行为，人们知之甚少。这一建议建立 我的实验室最近发现，LIM蛋白，zyxin，从成纤维细胞灶迅速动员， 粘附到肌动蛋白应力纤维，以响应外部施加的单轴循环拉伸。动员 zyxin对物理张力的反应依赖于基于整合素的粘附。细胞暴露于 机械刺激导致肌动蛋白应力纤维增强和细胞骨架垂直排列 拉伸向量。通过比较野生型和zyxin缺失的成纤维细胞，我们确定zyxin是 对机械张力引起的肌动蛋白应力纤维的增厚至关重要。的 拟议中的研究将确定zyxin有助于细胞的分子机制， 对身体压力的反应。首先，我们将探索刺激zyxin变化的信号 响应机械应力的定位和功能。其次，我们将探讨整合素如何激活 并且信号传导响应于机械应力而被调节。第三，我们将定义分子 应力纤维因拉伸而增强的机制。第四，我们将审问 拉伸调节基因表达的机制。这些研究提供了一个框架， 细胞对机械信号的反应。从分子水平理解细胞如何对 机械应力可能最终提示心肌病的治疗干预策略， 骨质疏松症和纤维化疾病，所有病理状况都是由响应于 机械提示

Integrin-dependent adhesion and signaling are required for cell motility, survival, and responsiveness to mechanical cues. Cells of the respiratory, cardiovascular, musculoskeletal, and urogenital systems are exposed to physical tension as part of their normal physiology. Cells respond and adapt to mechanical stress by remodeling their actin cytoskeletons and adopting new gene expression programs. Despite the critical importance of mechanical signals for embryonic development, wound healing, and tissue homeostasis, little is understood about how physical force influences cell behavior. This proposal builds on a recent discovery of my lab that the LIM protein, zyxin, is rapidly mobilized from fibroblast focal adhesions to actin stress fibers in response to externally applied, uniaxial, cyclic stretch. The mobilization of zyxin in response to physical tension depends on integrin-based adhesion. Exposure of cells to mechanical stimulation results in actin stress fiber reinforcement and cytoskeletal alignment perpendicular to the stretch vector. By comparing wild-type and zyxin-null fibroblasts, we determined that zyxin is essential for the thickening of actin stress fibers that occurs in response to mechanical tension. The proposed research will define the molecular mechanism by which zyxin contributes to the cellular responsiveness to physical stress. First, we will explore the signals that stimulate changes in zyxin localization and function in response to mechanical stress. Second, we will explore how integrin activation and signaling are regulated in response to mechanical stress. Third, we will define the molecular mechanism by which stress fibers are reinforced in response to stretch. Fourth, we will interrogate the mechanism of stretch-modulated gene expression. These studies provide a framework for understanding cell signaling in response to mechanical cues. A molecular understanding of how cells respond to mechanical stress may ultimately suggest strategies for therapeutic intervention in cardiomyopathy, osteoporosis, and fibrotic disorders, all pathological conditions driven by signaling in response to mechanical cues.