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性以来一直被广泛研究。 研究表明，培养中的细胞对其弹性模数的差异做出反应 环境。硬度传感已经在各种环境中被展示，例如开发， 癌症、伤口愈合和纤维化。细胞如何感知僵硬仍不清楚，部分原因是 缺乏准确定义细胞感觉的定量数据，特别是在体内。在……里面 特别是，粘弹性和非线性(应变相关)弹性的性质以及 正常组织和疾病组织的机械可塑性还没有得到充分的表征，而且 这些力学参数对细胞刚度感知和行为的贡献不是 明白了。这一建议将弹性研究扩展到包括额外的生物学方面 相关参数，重点是耗散过程的作用，并提供了潜在的 重新评估当前的机械生物学模型，发展时间依赖作用的新概念 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 和随机模型来分析离合器(即焦点粘连)形成的动力学 在细胞和底物之间。我们建议研究ECM对粘度、塑性的影响 和非线性弹性对细胞扩散和局部黏附生长的影响；具体地说，开发一种 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 关于粘性和塑性耗散可以与研究充分的情况一样重要的假设 在确定细胞响应时的弹性模数。我们建议a)评估粘性和 细胞力学传感矩阵的弹性成分，b)模型和测量效应 胶原蛋白基质中纤维重排的机械传感、粘合动力学和 细胞行为和c)定义了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。

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.