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.

自开创以来，力学在确定细胞表型中的作用已得到深入研究 研究表明，培养中的细胞对其弹性模量的差异做出反应 环境。刚度传感已在开发、 癌症、伤口愈合和纤维化。细胞如何感知硬度仍不清楚，部分原因是 缺乏准确定义细胞感知的定量数据，尤其是在体内。在 特别是粘弹性和非线性（应变相关）弹性的性质和 正常组织和患病组织的机械可塑性尚未得到充分表征，并且 这些机械参数对细胞刚度传感和行为的贡献不是 明白了。该提案扩展了弹性研究以涵盖更多的生物学 相关参数，重点关注耗散过程的作用，并提供了潜力 重新评估当前的机械生物学模型并发展时间依赖性作用的新概念 生物学背景下的力学。 拟议的工作建立在我们最近进行的一系列调查的基础上，我们在这些调查中开发了 描述纤维 ECM 非线性和耗散行为的理论模型 和随机模型来分析形成的离合器（即粘着斑）的动力学 位于细胞和基质之间。我们建议研究 ECM 粘度、塑性的影响 细胞扩散和粘着斑生长的非线性弹性；具体来说，开发一个 详细了解内在细胞之间的竞争关系 确定 ECM 中耗散过程的时间尺度和特征时间尺度，基于 假设粘性和塑性耗散与经过充分研究的案例一样重要 弹性模量在确定细胞反应中的作用。我们建议 a) 评估粘性和粘性的作用 基质的弹性成分对细胞机械传感的影响，b) 建模并测量效果 胶原基质中的纤维重新排列对机械传感、粘附动力学和 细胞行为和 c) 定义粘塑性重塑之间的相互关系 胶原蛋白网络和细胞机械传感。