Structure and Function of cell adhesion sites

细胞粘附位点的结构和功能

基本信息

批准号：
8299208
负责人：
MARY C. BECKERLE
金额：
$ 12.09万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299208
关键词：
Actins Adaptive Behaviors Address Adhesions Adopted Apoptosis Binding Cardiac Cardiomyopathies Cardiovascular system Cell Adhesion Cell Nucleus Cell Surface Receptors Cells Cellular biology Chemicals Cues Cytoskeleton Development Disease ECM receptor Embryonic Development Family Fibroblasts Fibrosis Focal Adhesions Funding Gene Expression Genes Genetic Genetic Transcription Genitourinary system Goals Homeostasis Integrins Ligand Binding Ligands Locomotion Lung Maps Mechanical Stimulation Mechanical Stress Mechanics Mediating Molecular Molecular Genetics Molecular Profiling Mus Musculoskeletal Null Lymphocytes Osteoporosis Pathway interactions Phosphorylation Site Physiology Play Proteins Psychological reinforcement Regulatory Pathway Research Research Personnel Role Serum Response Factor Signal Transduction Site Site-Directed Mutagenesis Stress Stress Fibers Stretching Structure Testing Therapeutic Intervention Tissues Tyrosine Phosphorylation Work Wound Healing ZYX gene base cell behavior cell motility design frontier human BCAR1 protein pressure programs respiratory response vasodilator-stimulated phosphoprotein vector

项目摘要

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.

整合素依赖性粘附和信号传导是细胞运动、存活和对细胞的反应性所必需的机械提示。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是作为正常生理的一部分，承受身体紧张。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。尽管机械信号对于胚胎发育、伤口愈合和组织至关重要由于体内平衡，人们对物理力如何影响细胞行为知之甚少。该提案构建我的实验室最近发现 LIM 蛋白 zyxin 可以从成纤维细胞灶中快速动员起来响应外部施加的单轴循环拉伸而粘附到肌动蛋白应力纤维。动员 zyxin 对物理张力的反应取决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到拉伸向量。通过比较野生型和 zyxin-null 成纤维细胞，我们确定 zyxin 是对于响应机械张力而发生的肌动蛋白应力纤维的增厚至关重要。这拟议的研究将确定 zyxin 促进细胞对身体压力的反应。首先，我们将探讨刺激 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和信号传导根据机械应力进行调节。第三，我们来定义分子应力纤维响应拉伸而增强的机制。第四，我们会询问拉伸调节基因表达的机制。这些研究提供了一个理解框架细胞信号响应机械信号。从分子角度理解细胞如何响应机械应力可能最终提出心肌病治疗干预的策略，骨质疏松症和纤维化疾病，所有由信号响应驱动的病理状况机械提示。