Structure and Function of cell adhesion sites

描述(由申请人提供)：整合素依赖的黏附和信号是细胞运动、存活和对机械提示的反应所必需的。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暴露在生理压力下，这是它们正常生理的一部分。细胞通过重塑其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压力。尽管机械信号对胚胎发育、伤口愈合和组织动态平衡至关重要，但人们对物理力量如何影响细胞行为知之甚少。这一建议建立在我的实验室最近的一项发现之上，即LIM蛋白Zysin在外部施加单轴循环拉伸时，会从成纤维细胞的焦点粘连迅速动员到肌动蛋白应激纤维上。凝集素对物理张力的反应依赖于基于整合素的黏附。细胞暴露在机械刺激下会导致肌动蛋白应力纤维增强和细胞骨架垂直于拉伸矢量排列。通过比较野生型和凝集素缺失的成纤维细胞，我们确定凝集素对于肌动蛋白应激纤维的增厚是必不可少的，而肌动蛋白应激纤维是对机械张力的反应。这项拟议的研究将确定齐新对细胞对物理压力的反应的分子机制。首先，我们将探索在机械应力作用下，刺激Zysin定位和功能变化的信号。其次，我们将探索整合素的激活和信号如何在机械压力下被调节。第三，我们将定义应力纤维因拉伸而增强的分子机制。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信号对机械信号的反应提供了一个框架。对细胞如何应对机械应力的分子理解最终可能会为心肌病、骨质疏松症和纤维化疾病的治疗干预提供策略，所有这些病理状态都是由响应机械信号的信号驱动的。

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.