Pathological consequences of altered tissue mechanics in fibrosis

项目摘要 细胞和组织是机械敏感的。许多 和 包括肝脏在内的组织受到机械应力 在多个时间和长度尺度上变形;这些都可以在疾病中改变并驱动疾病。我们 已经使用体外实验和理论来表明组织力学是一种涌现的性质， 由三种成分引起并需要三种成分：细胞外基质（ECM）的复杂纤维网络， 网络中的细胞，以及施加在组合系统上的力。我们过去三年的工作 项目期间专门研究了复杂纤维网络的微结构和特征， 细胞内包涵体和细胞骨架网络对细胞力学的影响，以及粘弹性对细胞力学的影响。 和组织行为。总的来说，这项工作导致了组织的多轴模型的发展。 然而，值得注意的是，虽然在理解组织弹性方面已经取得了重大进展，但粘性耗散 和塑性的研究很少，力学和结构之间的关系-到这一点， 一个可以从另一个预测-仍然知之甚少。 这一竞争性更新提案的总体目标是证明体内适用性和预测性 我们所定义的概念的价值。具体而言，我们建议确定个人的贡献 组织的组成部分，以紧急组织力学和这些力学对细胞行为的影响。我们 与以前的项目周期一样，本提案中的模型组织是正常的、纤维化的和硬化的肝脏。虽然 我们的研究结果将普遍适用于身体的其他器官。 我们假设，包括粘性耗散在内的组织力学可以通过以下方程来描述和预测： 整合ECM纤维网络、细胞和所施加的力的特征。有三个具体的 目的：1）确定基质结构与粘性耗散、弹性和塑性的关系 在正常和患病组织中; 2）确定细胞特性和细胞基质组织对组织的影响 力学，特别是粘度;以及3）测量正常组织中的组织固体应力和间质流体压力。 和患病组织，并定义这些力对组织力学的影响，包括耗散。这些 具体目标将使用实验和理论以及机器学习方法来预测 结构和力学之间的关系，指导干预，并产生一个统一的和治疗- 疾病中组织力学的目标模型。 我们以前已经确定了许多组织力学的设计原则。在拟议的工作中， 我们将进一步定义组织力学的三个基本要素的关键组成部分， 我们可以从结构预测力学（及其对细胞和新陈代谢的影响）。因此，该提案具有 有可能回答组织力学中的基本问题，并提出操纵方法 机械学在临床上的应用

PROJECT SUMMARY Cells and tissues are mechanosensitive. Many and tissues, including the liver, are subjected to mechanical stresses deformed over multiple time and length scales; these can both be altered in disease and drive disease.We have used in vitro experimentation and theory to show that tissue mechanics are an emergent property, arising from and requiring three components: the complex fibrous network of the extracellular matrix (ECM), the cells within that network, and the forces applied to the combined system. Our work in the three years of the past project period has specifically examined the microarchitecture and features of complex fibrous networks, the role of cytoplasmic inclusions and cytoskeletal networks on cell mechanics, and the impact of viscoelasticity on cell and tissue behavior. Collectively, this work has resulted in the development of a multi-axial model of a tissue. Notably, however, while significant strides have been made in understanding tissue elasticity, viscous dissipation and plasticity have been little studied, and the relationship between mechanics and structure – to the point that one can be predicted from the other – remains poorly understood. The overall goal in this competing renewal proposal is to demonstrate the in vivo applicability and predictive value of the concepts we have defined. Specifically, we propose to determine the contribution of the individual components of tissues to emergent tissue mechanics and the impact of these mechanics on cell behavior. Our model tissue in this proposal, as in previous project periods, is the normal, fibrotic, and cirrhotic liver. although our findings will be generally applicable to other organs in the body. We hypothesize that tissue mechanics including viscous dissipation can be described and predicted by integrating the features of the ECM fibrous network, the cells, and the applied forces. There are three specific aims: 1) to determine the relationships between matrix structure and viscous dissipation, elasticity, and plasticity in normal and diseased tissue; 2) to determine the impact of cell properties and cell-matrix organization on tissue mechanics, particularly viscosity; and 3) to measure tissue solid stress and interstitial fluid pressure in normal and diseased tissue and to define the impact of these forces on tissue mechanics, including dissipation. These specific aims will use experimentation and theory as well as machine learning approaches to predict the relationship between structure and mechanics, guide interventions, and generate a unified and therapeutically- targetable model of tissue mechanics in disease. We have previously identified many of the design principles underlying tissue mechanics. In the proposed work, we will further define the critical components of the three elements underlying tissue mechanics, asking whether we can predict mechanics (and their effects on cells and metabolism) from structure. This proposal thus has the potential to answer fundamental questions in tissue mechanics, and to suggest approaches to manipulating mechanics in clinically-relevant ways.