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.

项目摘要 细胞和组织是机械敏感的。包括肝脏在内的许多组织都受到机械应力的作用 并以不同的幅度和速度变形，这些可以在疾病中改变。当机械性能 当组织发生变化时，如纤维化，或当压力异常时，如血管压力增加，细胞 异常变形，导致细胞功能改变，可引发或加重疾病。设计 然而，确定组织力学的原理在很大程度上是未知的。而粘弹性的 交联的半柔性聚合物网络（在内部细胞骨架和细胞外 基质（ECM））通常被认为主导组织力学，即软组织的机械响应 和半柔性聚合物凝胶在许多方面彼此相反。三维组织切片 而半柔性生物聚合物网络在压缩时软化 和扩展。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， 解释基质或细胞性质的变化如何改变组织的力学性质 发生在疾病中。 我们建议扩大在该提案的前三年资助期间产生的知识， 研究纤维基质在组织和细胞力学中的作用。具体来说，我们将制定一个更详细的 了解纤维网络与细胞和组织对细胞反应之间的关系- 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初步工作， 模型组织，正常和纤维化肝脏，但研究结果将普遍适用于器官和软组织 在体内我们将探讨复杂的纤维网络在不同时间和长度的组织行为中的作用 尺度，基于我们的工作假设，纤维网络是组织力学的关键决定因素 以及组织内细胞的行为。三个具体目标是：1）确定纤维的作用 组织间质基质在真实的和模型组织的机械响应性中的作用，并开发多轴 简单组织的力学模型; 2）确定游离和蛋白聚糖结合的GAG在胶原中的作用 纤维网络和组织力学; 3）定义确定可塑性（持久性）的机制 组织尺度的基质重塑。 为了所有的目标，我们将进行实验和理论工作，最终目标是了解 细胞和组织在不同生理相关基质和机械环境中的行为。这些研究 将使我们能够更好地了解组织力学的有害变化， 据记载，其有助于（而不是简单地由）疾病如纤维化的进展。最后， 它们可能导致针对患病组织的特定机械特征的创新性新治疗。