Structure and Function of cell adhesion sites

整合素依赖的黏附和信号转导是细胞运动、存活和应答所必需的 机械的暗示。呼吸、心血管、肌肉骨骼和泌尿生殖系统的细胞 暴露在身体紧张状态下是他们正常生理的一部分。细胞对机械反应和适应 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、伤口愈合和组织的重要作用 动态平衡，人们对物理力量如何影响细胞行为知之甚少。这项建议建立了 根据我的实验室最近的一项发现，LIM蛋白Zysin可以从成纤维细胞焦点快速动员起来 粘连到肌动蛋白应激纤维上，以响应外部施加的单轴、循环拉伸。动员 自新对物理张力的反应依赖于基于整合素的粘附力。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 到拉伸向量。通过比较野生型和凝集素缺失的成纤维细胞，我们确定凝集素是 对于肌动蛋白应激纤维的增厚是必不可少的，这是对机械张力的反应。这个 拟议中的研究将定义齐新对细胞的贡献的分子机制 对身体压力的反应能力。首先，我们将探索刺激自信变化的信号 在机械应力作用下的定位和功能。第二，我们将探索整合素是如何激活的 信号是根据机械应力进行调节的。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。这些研究为理解 细胞对机械信号的反应。对细胞如何反应的分子理解 机械应激可能最终建议心肌病的治疗干预策略， 骨质疏松症和纤维性疾病，所有这些病理状态都是由信号反应驱动的 机械的暗示。

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.