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：
7929091
负责人：
MARY C. BECKERLE
金额：
$ 24.87万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929091
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 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.

整合素依赖性的粘附和信号传导是细胞运动，生存性和对机械提示。呼吸道，心血管，肌肉骨骼和泌尿生殖器系统的细胞是作为其正常生理学的一部分，暴露于身体张力。细胞响应并适应机械通过重塑其肌动蛋白细胞骨架并采用新的基因表达程序来压力。尽管有机械信号对于胚胎发育，伤口愈合和组织的至关重要体内平衡，几乎没有什么理解的物理力如何影响细胞行为。该建议建立在最近发现我的实验室的发现，lim蛋白Zyxin从成纤维细胞局灶性迅速动员响应于外部应用，单轴循环拉伸的肌动蛋白应激纤维的粘附。动员 Zyxin响应物理张力的响应取决于基于整合素的粘附。暴露于细胞机械刺激导致肌动蛋白应力纤维增强和垂直的细胞骨架比对到拉伸矢量。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激纤维的增厚必不可少的。这拟议的研究将定义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，我们将探讨整联蛋白如何激活并根据机械应力调节信号传导。第三，我们将定义分子应力纤维响应拉伸而加强应力纤维的机制。第四，我们将审问拉伸调节基因表达的机制。这些研究为理解提供了一个框架响应机械提示的细胞信号传导。对细胞如何反应的分子理解机械压力最终可能提出了心肌病治疗干预的策略，骨质疏松症和纤维性疾病，所有病理状况由信号驱动的所有病理状况。机械提示。