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Dynamics of Actin in Normal and Transformed Cells

正常细胞和转化细胞中肌动蛋白的动态

基本信息

批准号：
8067851
负责人：
Yu-li Wang
金额：
$ 48.72万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8067851
关键词：
Ablation Actins Address Adhesions Adhesives Affect Atomic Force Microscopy Cancerous Cell Shape Cells Centrosome Chemicals Cytoskeleton Differentiation and Growth Dimensions Dorsal Embryonic Development Environment Extracellular Matrix Fluorescence Fluorescence Resonance Energy Transfer Focal Adhesions Gene Combinations Genes Goals Health Home environment Image Imaging Techniques Integrins Lead Life Location Malignant Neoplasms Maps Mechanics Mediating Medical Methods Microfabrication Micromanipulation Microtubules Molecular Morphology Normal Cell Normal Range Optics Outcome Pathologic Processes Pattern Physical environment Physiological Processes Play Positioning Attribute Process Proteins Public Health Regenerative Medicine Regulation of Cell Shape Research Resolution Role Screening procedure Shapes Signal Transduction Site Surface Testing Tissues Traction UV sensitive Wound Healing base cell motility cell transformation cellular imaging density image processing in vivo innovation mathematical model migration molecular scale novel particle research study response sensor stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the mechanisms of a wide range of functions performed by the actin cytoskeleton. The proposed research will focus on the basic principles that control cell shape and migration, which play an important role in numerous physiological and pathological processes including embryonic development, wound healing, and metastatic invasion. In addition, control of cell shape and migration represents a bottleneck in regenerative medicine with few effective strategies. While rapid advances have been made on identifying and characterizing the molecular components, the fundamental rules governing the responses of these functions to the physical environment remain largely unknown. The study will combine powerful optical, mechanical, chemical, microengineering, and mathematical approaches to address the responses of adherent cells to substrate rigidity and topography, which are known to have profound effects on cell shape and migration, as well as downstream processes including growth and differentiation. The first aim will characterize cellular responses to rigidity, by determining the size scale of the sensor. The experiments will also test a hypothetical universal mechanism for sensing mechanical signals, and investigate the possible role of rigidity sensing in cancer invasion. The second aim will identify key parameters that determine cellular responses to the geometry of adhesive substrates. In addition, the experiments will test potential mechanisms of geometry sensing, including one based on differential tension at adhesion sites and the other on differential microtubule density and/or dynamics. The third aim will probe the mechanism that allows cells to distinguish 3D environments from 2D surfaces. The experiments will address the topographic requirements and the possible involvement of contractile forces, cortical rigidity, and microtubule positioning. The project will take full advantage of microfabricated substrates, in addition to other innovative approaches from photo- modulation, micromanipulation, to image processing. Cells will be manipulated with pharmacological and gene ablation/silencing techniques, and imaged with high-resolution confocal and total internal reflection fluorescence optics. The fundamental principles revealed by these experiments will impact a broad range of medical issues related directly or indirectly to the regulation of cell shape and migration. PUBLIC HEALTH REVELANCE: There is now extensive evidence that physical and topographical signals, including mechanical forces, rigidity, and geometric patterns, have profound effects on cell shape and migration, which in turn affect a wide range of normal and pathological processes from cancer invasion to stem cell differentiation. However, while cellular responses to chemical interactions have been studied extensively, much less is known about their responses to these non-chemical signals, partially due to the limitations in conventional experimental methods. The proposed experiments will apply highly innovative approaches to overcome the barrier, and to obtain crucial information for understanding and treating many health issues related to cell shape control and cell migration.

描述（由申请人提供）：该项目的长期目标是了解肌动蛋白细胞骨架执行的广泛功能的机制。拟议的研究将重点关注控制细胞形状和迁移的基本原理，这些原理在胚胎发育、伤口愈合和转移侵袭等众多生理和病理过程中发挥着重要作用。此外，细胞形状和迁移的控制是再生医学的瓶颈，缺乏有效的策略。尽管在识别和表征分子成分方面取得了快速进展，但控制这些功能对物理环境的响应的基本规则仍然很大程度上未知。该研究将结合强大的光学、机械、化学、微工程和数学方法来解决贴壁细胞对基质刚性和形貌的反应，众所周知，这对细胞形状和迁移以及包括生长和分化在内的下游过程具有深远的影响。第一个目标是通过确定传感器的尺寸来表征细胞对刚性的反应。这些实验还将测试一种假设的用于传感机械信号的通用机制，并研究刚性传感在癌症侵袭中的可能作用。第二个目标是确定决定细胞对粘合基底几何形状反应的关键参数。此外，这些实验将测试几何传感的潜在机制，包括一种基于粘附位点差异张力的机制，另一种基于微管密度和/或动力学差异的机制。第三个目标将探讨细胞区分 3D 环境和 2D 表面的机制。实验将解决地形要求以及可能涉及的收缩力、皮质刚性和微管定位。除了光调制、显微操作和图像处理等其他创新方法外，该项目还将充分利用微加工基板。将通过药理学和基因消融/沉默技术来操纵细胞，并使用高分辨率共焦和全内反射荧光光学器件进行成像。这些实验揭示的基本原理将影响与细胞形状和迁移调节直接或间接相关的广泛医学问题。公众健康启示：现在有大量证据表明，物理和地形信号，包括机械力、刚性和几何图案，对细胞形状和迁移具有深远影响，进而影响从癌症侵袭到干细胞分化的广泛正常和病理过程。然而，虽然细胞对化学相互作用的反应已被广泛研究，但人们对它们对这些非化学信号的反应知之甚少，部分原因是传统实验方法的局限性。拟议的实验将应用高度创新的方法来克服障碍，并获得理解和治疗与细胞形状控制和细胞迁移相关的许多健康问题的关键信息。