Pathological consequences of altered tissue mechanics in fibrosis

纤维化过程中组织力学改变的病理后果

• 批准号: 10240476
• 负责人: Paul A Janmey
• 金额: $ 49.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240476
• 关键词: 3-Dimensional; Abnormal Cell; Achievement; Adhesions; Behavior; Biopolymers; Blood Vessels; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Cicatrix; Collagen; Complex; Cytoskeleton; Disease; Disease Progression; Elasticity; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Funding; Gel; Glycosaminoglycans; Goals; Knowledge; Lead; Length; Liver; Liver Fibrosis; Mechanical Stress; Mechanics; Modeling; Nature; Non-linear Models; Organ; Pathologic; Pattern; Phenotype; Physiological; Polymers; Property; Proteoglycan; Role; Stress; Structure; Theoretical Studies; Theoretical model; Time; Tissue Model; Tissues; Viscosity; Work; base; cell behavior; crosslink; design; experimental study; flexibility; innovation; interstitial; mechanical force; mechanical properties; novel; novel strategies; pressure; prevent; response; soft tissue; theories; viscoelasticity

PROJECT SUMMARY Cells and tissues are mechanosensitive. Many tissues, including the liver, are subjected to mechanical stresses and deformed at varying magnitudes and rates that can be altered in disease. When the mechanical properties of tissues change, as in fibrosis, or when stresses are abnormal, as with increased vascular pressures, cells are abnormally deformed, with resulting changes in cellular function that can initiate or augment disease. The design principles that determine tissue mechanics, however, are largely unknown. While the viscoelasticity of crosslinked semi-flexible polymer networks (ubiquitous in both the internal cytoskeleton and the extracellular matrix (ECM)) is generally assumed to dominate tissue mechanics, the mechanical responses of soft tissues and semiflexible polymer gels are the opposite of each other in many respects. Three-dimensional tissues stiffen in compression and mildly soften in extension, whereas semiflexible biopolymer networks soften in compression and stiffen in extension. Our overall goal is to use experimental and theoretical studies to determine how the presence of cells within fibrous networks can explain the viscoelastic response of intact tissues and thereby help explain how changes in the properties of either the matrix or the cells can alter the tissue mechanical properties that occur in disease. We propose to expand the knowledge generated during the first three years of funding of this proposal to further study the role of fibrous matrices in tissue and cell mechanics. Specifically, we will develop a more detailed understanding of the relationship between fibrous networks and cell and tissue responses to cell- generated or externally applied forces. This work will capitalize on our expertise and preliminary work on a model tissue, the normal and fibrotic liver, but the findings will be generally applicable to organs and soft tissues in the body. We will explore the role of complex fibrous networks in tissue behavior at various time and length scales, basing our work on the hypothesis that fibrous networks are critical determinants of tissue mechanics and of the behavior of cells within tissues. The three specific aims are to: 1) Define the role of the fibrous interstitial matrix of tissues in the mechano-responsiveness of real and model tissues and develop a multiaxial mechanical model of a simple tissue; 2) Determine the role of free and proteoglycan-bound GAGs in collagen fibrous networks and tissue mechanics; and 3) Define mechanisms that determine the plasticity (permanence) of tissue-scale matrix remodeling. For all aims, we will carry out both experimental and theoretical work, with the ultimate goal of understanding cell and tissue behavior in different physiologically-relevant matrix and mechanical environments. These studies will enable us to better understand the deleterious changes in tissue mechanics that are increasingly documented to contribute to (rather than simply result from) progression of diseases such as fibrosis. Ultimately, they may lead to innovative new treatments targeting specific mechanical features of diseased tissues.

项目总结 细胞和组织是机械敏感的。许多组织，包括肝脏，都会受到机械压力。 并以不同的幅度和速度变形，这些变形可以在疾病中改变。当机械性能发生变化时 组织的变化，如纤维化，或当应力异常时，如血管压力增加，细胞 不正常的畸形，导致细胞功能的改变，从而引发或加重疾病。设计 然而，决定组织力学的原理在很大程度上是未知的。而材料的粘弹性 交联型半柔性聚合物网络(广泛存在于细胞内和细胞外 基质(ECM)通常被认为主导组织力学，即软组织的机械反应 而半柔性聚合物凝胶在许多方面是相反的。三维组织变硬 在压缩时略有软化，而半柔性生物聚合物网络在压缩时软化 并在延伸中变得僵硬。我们的总体目标是利用实验和理论研究来确定 纤维网络中细胞的存在可以解释完整组织的粘弹性反应，从而有助于 解释基质或细胞性质的改变如何改变组织的机械性质 在疾病中发生。 我们建议扩大在这项提议的头三年提供资金期间产生的知识，以进一步 研究纤维基质在组织和细胞力学中的作用。具体地说，我们将制定更详细的 了解纤维网络与细胞和组织对细胞的反应之间的关系 产生的或外部施加的力。这项工作将利用我们的专业知识和关于 模型组织，正常和纤维化的肝脏，但这一发现将普遍适用于器官和软组织 在身体里。我们将探索复杂的纤维网络在不同时间和长度的组织行为中的作用 我们的工作基于纤维网络是组织力学的关键决定因素这一假设 以及组织内细胞的行为。三个具体的目标是：1)确定纤维的作用 组织间质基质在真实组织和模型组织中的机械反应性及其发展的多轴 简单组织的力学模型；2)确定游离和蛋白多糖结合的GAG在胶原中的作用 纤维网络和组织力学；以及3)定义决定可塑性(永久性)的机制。 组织规模的基质重塑。 对于所有的目标，我们将进行实验和理论工作，最终目的是了解 细胞和组织在不同生理相关的基质和机械环境中的行为。这些研究 将使我们能够更好地理解组织力学中日益严重的有害变化 被证明是促进(而不是简单地导致)诸如纤维化等疾病的进展的。最终， 它们可能导致针对疾病组织的特定机械特征的创新治疗。