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

基本信息

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
项目类别：
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

项目摘要

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）：细胞对环境中的机械力响应。这些力对细胞表型可能与可溶性因子一样重要，具有类似的复杂作用。特别是，细胞对环境的刚度产生的机械张力调节了大多数的行为（如果不是全部）细胞类型。在过去的十年中，矩阵刚度作为调节细胞形状和功能的机制的重要性已经越来越多地研究了，现在有充分的证据表明，僵硬的变化不仅与疾病相关，而且有助于其发育。研究组织僵硬在病理学中的作用的局限性是对细胞和组织弹性模量的独家强调，该模量经常被报道为与时间或变形无关的常数（应变）。合成底物已被广泛用于研究对底物刚度的细胞反应，但与生物组织具有许多显着差异：它们是线性弹性的，而大多数生物学材料都表现出非线性〜它们表现出粘度，尽管生物学材料是粘弹性的，但它们是粘弹性的，而不是三二维，而不是三二维。因此，尽管细胞清楚地响应了弹性模量的变化，但粘度和非线性对细胞和组织的影响也不清楚，即使这些因素可能是机械生理环境中细胞行为的主要决定因素。我们假设组织内部或人工底物在组织内部或人工底物的机械感应具有特征性的长度和时间尺度，并且非线性弹性和粘度是在短和长范围内驱动细胞行为和组织组织的生物组织的重要特性。我们的目标是开发组织的机械模型，并确定正常和受伤时各种机械特征与该组织的细胞行为和结构特征的生物学相关性。我们将使用正常和纤维化肝脏作为模型组织，因为我们工作的一般原理将适用于多种组织，但肝脏力学的初步表征广泛。我们有三个具体的目的：1）对正常和纤维化肝脏进行详细的机械表征，并开发和测试肝脏的机械模型，突出了细胞的相对贡献和基质〜2），以发展和表征新型的粘弹性底物，以模仿正常和纤维化乳液的粘层，以确定各个细胞的粘弹性，以确定这些细胞的响应，以确定这些细胞的这些细胞，从底物〜和3）以计算对大规模组织在纤维化中模式中的作用进行计算模型和实验测试。