Structure and Function of cell adhesion sites

描述（由申请人提供）：整合素依赖性粘附和信号传导是细胞运动、存活和对机械信号的反应所必需的。呼吸、心血管、肌肉骨骼和泌尿生殖系统的细胞作为其正常生理的一部分暴露于物理张力。细胞通过重塑肌动蛋白细胞骨架和采用新的基因表达程序来响应和适应机械应力。尽管机械信号对胚胎发育、伤口愈合和组织稳态至关重要，但人们对物理力如何影响细胞行为知之甚少。这个建议建立在我的实验室最近发现的LIM蛋白，zyxin，是迅速动员从成纤维细胞粘着斑肌动蛋白应力纤维响应外部施加，单轴，循环拉伸。结合蛋白的动员响应于物理张力依赖于整合素为基础的粘附。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排列垂直于拉伸矢量。通过比较野生型和zyxin缺失的成纤维细胞，我们确定zyxin对于响应机械张力而发生的肌动蛋白应力纤维增厚至关重要。这项研究将明确zyxin促进细胞对物理应激反应的分子机制。首先，我们将探索刺激zyxin定位和功能变化的信号，以响应机械应力。其次，我们将探索整合素激活和信号传导如何响应机械应力而受到调节。第三，我们将定义的分子机制，应力纤维被加强，以响应拉伸。第四，我们将询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提供了一个框架。对细胞如何响应机械应力的分子理解可能最终为心肌病，骨质疏松症和纤维化疾病的治疗干预提供策略，所有病理条件都是由响应机械提示的信号驱动的。

DESCRIPTION (provided by applicant): 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.