Pathological consequences of altered tissue mechanics in fibrosis

项目总结 细胞和组织是机械敏感的。许多 和 组织，包括肝脏，会受到机械压力。 在多个时间和长度尺度上变形；这些都可以在疾病和驱动疾病中改变。我们 已经用体外实验和理论证明了组织力学是一种紧急性质， 产生和需要三个组成部分：细胞外基质(ECM)的复杂纤维网络， 该网络中的单元格，以及应用于组合系统的力。我们过去三年的工作 项目期内专门考察了微体系结构和复杂光纤网络的特点、作用 细胞质包裹体和细胞骨架网络对细胞力学的影响，以及粘弹性对细胞的影响 和组织行为。总而言之，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，尽管在理解组织弹性方面取得了重大进展，但粘性消散 和塑性的研究很少，力学和结构之间的关系-到了 其中一个可以从另一个中预测出来--仍然知之甚少。 这个相互竞争的更新提案的总体目标是展示在体内的适用性和预测性 我们定义的概念的价值。具体来说，我们建议确定个人的贡献 新出现的组织力学的组织成分以及这些力学对细胞行为的影响。我们的 本提案中的模型组织与之前的项目期间一样，是正常的、纤维化的和肝硬变的肝脏。虽然 我们的发现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用以下公式来描述和预测 结合ECM纤维网络、细胞和作用力的特点。有三个具体的 目标：1)确定基质结构与粘性耗散、弹性和塑性之间的关系 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；3)在正常情况下测量组织固体应力和间质流体压力 和病变组织，并定义这些力对组织力学的影响，包括消散。这些 特定目标将使用实验和理论以及机器学习方法来预测 结构和力学的关系，指导干预，产生统一的和治疗上的- 疾病中的组织力学目标模型。 我们之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基础的三个要素的关键组成部分，询问是否 我们可以从结构中预测力学(及其对细胞和新陈代谢的影响)。因此，这项建议具有 有可能回答组织力学中的基本问题，并提出操作方法 以临床相关的方式研究力学。

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.