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: 8758936
• 负责人: Paul A Janmey
• 金额: $ 43.28万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758936
• 关键词: Adhesives; Affect; Animal Model; Behavior; Biocompatible Materials; Biological; Biological Models; Cell Communication; Cell Shape; Cell physiology; Cells; Characteristics; Chronic; Cirrhosis; Complex; Computer Simulation; Cues; Cytoskeleton; Development; Devices; Diagnostic tests; Disease; Elastic Tissue; Elasticity; Environment; Fibrosis; Glycosaminoglycans; Goals; Hepatocyte; In Vitro; Individual; Injury; Intervention; Lead; Length; Liver; Liver Fibrosis; Malignant Neoplasms; Measures; Mechanical Stress; Mechanics; Modeling; Morbidity - disease rate; Myofibroblast; Organ; Pathology; Pattern; Phenotype; Physiological; Process; Property; Proteins; Relative (related person); Reporting; Role; Signal Pathway; Staging; Surface; Testing; Time; Tissue Model; Tissues; Viscosity; Work; Wound Healing; cell behavior; cell type; injured; insight; mortality; novel; novel diagnostics; polyacrylamide; polydimethylsiloxane; public health relevance; response; response to injury; two-dimensional; viscoelasticity

DESCRIPTION (provided by applicant): Cells respond to mechanical forces in their environment. These forces are likely to be as important to cell phenotype as soluble factors, with similarly complex effects. In particular, mechanical tension generated by cells in response to the stiffness of their environment regulates the behavior of most (if not all) cell types. Over the last ten years, the importance of matrix stiffness as a mechanism for modulating cell shape and function has become increasingly studied, and there is now good evidence that changes in stiffness not only correlate with disease, but contribute to its development. A limitation of most current work studying the role of tissue stiffness in pathology is an exclusive emphasis on cell and tissue elastic modulus, which is frequently reported as a constant independent of time or deformation (strain). Synthetic substrates have been used extensively for studies of the cellular response to substrate stiffness, but have a numberof significant differences from biological tissues: they are linearly elastic, whereas most biologicl materials demonstrate non-linearity~ they fail to incorporate viscosity, although biologicl materials are viscoelastic~ and they are two-dimensional rather than three-dimensional. Thus, while cells clearly respond to changes in the elastic modulus, the impact of viscosity and non-linearity on cells and tissues is not understood even though these factors may be major determinants of cell behavior in mechanically physiological environments. We hypothesize that mechanosensing by cells within tissues or on artificial substrates has characteristic length and time scales and that non-linear elasticity and viscosity are important properties of biological tissues that drive cell behavior and tissue organizaton over both short and long ranges. Our goal is to develop a mechanical model of a tissue, and to determine the biological relevance of various mechanical features to cell behavior and architectural features of this tissue when normal and injured. We will use the normal and fibrotic liver as a model tissue, since there are extensive preliminary characterizations of liver mechanics, although the general principles of our work will be applicable to multiple tissues. We have three specific aims: 1) to carry out a detailed mechanical characterization of the normal and fibrotic liver, and to develop and test a mechanical model of the liver highlighting the relative contributions of cells and the matrix~ 2) to develop and characterize novel viscoelastic substrates that mimic the viscoelasticity of normal and fibrotic livers, and to determine the response of individual cells of the liver to these biologically relevant substrates~ and 3) to computationally model and experimentally test the role of mechanics in large-scale tissue patterning in fibrosis.

描述(由申请人提供)：细胞对其环境中的机械力做出反应。这些作用力对细胞表型的影响可能与可溶性因子一样重要，具有类似的复杂影响。特别是，细胞因其环境的僵硬而产生的机械张力调节了大多数(如果不是全部)的行为。 单元类型。在过去的十年中，基质硬度作为一种调节细胞形态和功能的机制的重要性得到了越来越多的研究，现在有很好的证据表明，硬度的变化不仅与疾病相关，而且有助于疾病的发展。目前研究组织僵硬在病理学中作用的大多数工作的局限性 唯一强调的是细胞和组织的弹性模数，它经常被报道为与时间或变形(应变)无关的常数。合成底物已被广泛用于研究细胞对底物硬度的反应，但与生物组织有许多显著的不同：它们是线性弹性的，而大多数生物材料表现出非线性~它们没有考虑粘度，尽管生物材料是粘弹性的，它们是二维的而不是三维的。因此，尽管细胞对弹性模数的变化有明显的反应，但粘性和非线性对细胞和组织的影响尚不清楚，即使这些因素可能是 在机械生理环境中细胞行为的主要决定因素。我们假设细胞在组织内或人工基质上的机械感知具有特定的长度和时间尺度，非线性弹性和粘性是生物组织的重要属性，它们在短范围和长范围内驱动细胞行为和组织结构。我们的目标是开发一种组织的机械模型， 并确定各种力学特征与正常和损伤时该组织的细胞行为和结构特征的生物学相关性。我们将使用正常的和纤维化的 肝脏作为一个模型组织，因为有广泛的肝脏力学的初步特征，尽管我们工作的一般原则将适用于多种组织。我们有三个具体的目标：1)对正常和纤维化的肝脏进行详细的力学表征，并开发和测试突出细胞和基质的相对贡献的肝脏的力学模型。2)开发和表征模拟正常和纤维化肝脏的粘弹性的新型粘弹性底物，并确定肝脏单个细胞对这些生物相关的反应。 3)计算建模和实验测试力学在大范围组织模式在纤维化中的作用。