Integration of elasticity, viscosity, and plasticity in cellular mechanosensing

细胞力传感中弹性、粘度和塑性的整合

• 批准号: 10246375
• 负责人: Vivek Shenoy
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246375
• 关键词: 3-Dimensional; Adhesions; Adhesives; Behavior; Binding; Biological; Case Study; Cell Adhesion; Cell physiology; Cells; Characteristics; Collagen; Computer Models; Data; Development; Disease; Disease Progression; Elasticity; Environment; Evolution; Extracellular Matrix; Feedback; Fiber; Fibrosis; Focal Adhesions; Gel; Generations; Goals; Growth; Homeostasis; In Vitro; Investigation; Lead; Ligands; Malignant Neoplasms; Measures; Mechanics; Modeling; Modulus; Motor; Mus; Nature; Phase; Phenotype; Physiological; Polymers; Process; Relaxation; Role; Role Concepts; Series; Stress; Stretching; Testing; Theoretical Studies; Theoretical model; Time; Tissue Model; Tissues; Traction; Viscosity; Work; base; cell behavior; cellular imaging; crosslink; design; experimental study; falls; in vivo; in vivo Model; innovation; mechanical properties; mechanotransduction; network models; response; spatiotemporal; theories; viscoelasticity; wound healing

The role of mechanics in determining cell phenotype has been intensely studied since pioneering studies showed that cells in culture respond to differences in the elastic modulus of their environment. Stiffness sensing has been demonstrated in such varied settings as development, cancer, wound healing and fibrosis. How cells sense stiffness remains unclear, partly because of a lack of quantitative data that define exactly what cells sense, especially in vivo. In particular, the nature of viscoelasticity and non-linear (strain-dependent) elasticity and mechanical plasticity in normal and diseased tissues is insufficiently characterized, and the contribution of these mechanical parameters to cell stiffness sensing and behavior is not understood. This proposal extends studies of elasticity to encompass additional biologically relevant parameters, with a focus on the role of dissipative processes, and offers the potential to reevaluate current models of mechanobiology and develop new concepts of the role of time dependent mechanics in biological contexts. The proposed work builds on a series of our recent investigations where we have developed theoretical models to describe the non-linear and dissipative behavior of fibrous ECMs and stochastic models to analyze the dynamics of clutches (i.e., focal adhesions) formed between the cell and a substrate. We propose to investigate the impact of ECM viscosity, plasticity and non-linear elasticity on cell spreading and focal adhesion growth; specifically, to develop a detailed understanding of the relationship between the competition between intrinsic cellular timescales and characteristic timescales that determine the dissipative processes in the ECM, based on the hypothesis that viscous and plastic dissipation can be as important as the well-studied case of elastic moduli in determining cell response. We propose to a) Assess the role of viscous and elastic constituents of a matrix on cellular mechanosensing, b) Model and measure the effect of fiber realignment in collagen matrices on mechanosensing, adhesion dynamics, and cellular behavior and c) Define the reciprocal relation between viscoplastic remodeling of collagen networks and cellular mechanosensing.

自开创性以来，就已经对机理在确定细胞表型中的作用进行了深入研究 研究表明，培养细胞对其弹性模量的差异反应 环境。在开发等各种设置中已证明了刚度感应 癌症，伤口愈合和纤维化。细胞如何感觉刚度仍不清楚，部分原因是 缺乏定量数据，这些数据准确地定义了哪些细胞感，尤其是体内。在 特别是粘弹性和非线性（应变依赖性）弹性的性质和 正常组织和患病组织中的机械可塑性不足以表征，并且 这些机械参数对细胞刚度感应和行为的贡献不是 理解。该建议扩展了弹性的研究，以涵盖其他生物学 相关参数，重点是耗散过程的作用，并提供了潜力 重新评估机械生物学的当前模型并开发有关时间依赖性作用的新概念 在生物学环境中的力学。 拟议的工作建立在我们最近开发的一系列调查基础上 描述纤维ECM的非线性和耗散行为的理论模型 和随机模型以分析形成离合器的动力学（即焦点粘连） 在细胞和基板之间。我们建议研究ECM粘度，可塑性的影响 以及细胞扩散和局灶性粘附生长的非线性弹性；具体来说，要开发一个 详细了解固有细胞之间的竞争之间的关系 确定ECM中耗散过程的时间表和特征时间尺度，基于ECM中的耗散过程 关于粘性和塑料耗散的假设可能与研究的情况一样重要 弹性模量在确定细胞反应时。我们建议a）评估粘性和 矩阵的弹性成分在细胞机械传感器上，b）模型并测量效果 在机械连感应，粘附动力学和 细胞行为和c）定义粘塑料重塑之间的相互关系 胶原蛋白网络和细胞机械感应。