Integration of elasticity, viscosity, and plasticity in cellular mechanosensing

力学在决定细胞表型中的作用自开创以来一直被深入研究， 研究表明，培养中的细胞对它们的弹性模量的差异作出反应。 环境刚度感测已经在各种环境中得到证明， 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 缺乏定量数据来准确定义细胞的感觉，特别是在体内。在 特别地，粘弹性和非线性（应变相关）弹性的性质， 正常和患病组织中的机械可塑性特征不充分， 这些机械参数对单元刚度感测和行为的贡献不是 明白这一建议扩展了弹性的研究，以包括额外的生物学 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 和随机模型来分析离合器的动力学（即，局灶性粘连） 在电池和基板之间。我们建议研究ECM粘度、可塑性 和非线性弹性对细胞铺展和粘着斑生长的影响;具体地说， 详细了解了细胞内竞争与细胞内 确定ECM中耗散过程的时间尺度和特征时间尺度， 假设粘性耗散和塑性耗散与已充分研究的情况一样重要， 弹性模量决定细胞反应。我们建议a）评估粘性和 基质的弹性成分对细胞机械感测的影响，B）建模并测量效果 胶原蛋白基质中的纤维重新排列对机械传感，粘附动力学， 细胞行为和c）定义粘塑性重塑之间的相互关系， 胶原网络和细胞机械传感。

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.