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 细胞和组织具有机械敏感性。许多组织，包括肝脏，都有机械应力 并以疾病可能改变的幅度和速率变化。当机械性能 组织的变化，如纤维化或应力异常时，与血管压力增加一样，细胞为 异常变形，导致细胞功能的变化可以引发或增强疾病。设计 但是，确定组织力学的原则在很大程度上尚不清楚。而粘弹性的 交联的半灵性聚合物网络（内部细胞骨架和细胞外无处不在 通常认为矩阵（ECM））主导组织力学，这是软组织的机械响应 在许多方面，半融合的聚合物凝胶彼此相反。三维组织变硬 在压缩中，延伸中有轻度软化，而半循环的生物聚合物网络在压缩方面软化 并延伸。我们的总体目标是使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响应，从而有助于 说明矩阵或细胞的性质的变化如何改变组织机械性能 这是在疾病中发生的。 我们建议扩大该提案资金前三年产生的知识，以进一步 研究纤维基质在组织和细胞力学中的作用。具体来说，我们将开发一个更详细的 了解纤维网络与细胞之间的关系以及组织对细胞的反应 产生或外部施加力。这项工作将利用我们的专业知识和初步工作 模型组织，正常和纤维化的肝脏，但发现通常适用于器官和软组织 在体内。我们将探索复杂纤维网络在各个时间和长度的组织行为中的作用 尺度，基于我们的工作，即纤维网络是组织力学的关键决定因素的假设 以及组织内细胞的行为。三个具体目的是：1）定义纤维的作用 在真实组织和模型组织的机械反应性中组织的间质基质，并发展多轴 简单组织的机械模型； 2）确定胶原蛋白中的自由和蛋白聚糖结合插科打的作用 纤维网络和组织力学； 3）定义确定可塑性（持久性）的机制 组织尺度基质重塑。 对于所有目标，我们将同时进行实验和理论工作，以理解的最终目标 在不同生理上的矩阵和机械环境中的细胞和组织行为。这些研究 将使我们能够更好地了解越来越多的组织力学变化 记录是为了（而不是简单地源于）诸如纤维化等疾病的进展。最终， 它们可能导致针对患病组织特定机械特征的创新新处理。