An Integrative Multi-Scale Model of Extracellular Matrix Mechanics in Vascular Re

血管再生中细胞外基质力学的综合多尺度模型

• 批准号: 8014856
• 负责人: Yanhang Katherine Zhang
• 金额: $ 28.51万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8014856
• 关键词: Adopted; Affect; Arteries; Arteriosclerosis; Behavior; Biochemical; Biological Assay; Biomechanics; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical; Collagen; Complement; Confocal Microscopy; Coupled; Coupling; Data; Development; Diagnostic; Disease; Elastin; Elements; Entropy; Experimental Models; Extracellular Matrix; Fiber; Goals; Heart; Malignant Neoplasms; Measures; Mechanics; Microbiology; Modeling; Molecular; Physics; Research; Research Personnel; Science; Smooth Muscle Myocytes; Statistical Mechanics; Stretching; Structural Protein; Structure; Study models; Testing; Tissues; United States; Validation; Vascular remodeling; Western World; Work; arterial stiffness; base; cardiovascular disorder therapy; crosslink; density; design; fibrillin; information model; interest; model development; multi-scale modeling; tool

DESCRIPTION (provided by applicant): With the current development of non-invasive diagnostics to more accurately measure the level of cardiovascular diseases (CVDs) clinically, a significant "platform science" component is better mechanistic understanding of underlying physics, such as structure-function mechanics of the arterial wall. Much of this fundamental understanding comes from the development and study of models for biomechanics, which will provide guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting in turn provides data for refining the physics models. In this project, we seek to develop a multiscale predictive mechanobiology model of extracellular matrix (ECM) mechanics from a fundamental mechanics perspective coupled with critical biophysical input, and to provide a clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. Such model will enable researchers and clinicians to probe basic mechanisms, and to assist in rational design of new therapies for CVD. Specific Aim 1: Create a multiscale predictive mechanobiology model of ECM mechanics. Molecular - fiber level: a statistical mechanics based approach is adopted to determine the strain energy change accompanying deformation of a single fiber. A freely joined chain (FJC) model will be adopted to describe the possible configurations, thus entropy, of a fiber during stretching. Inter-molecular cross-linking density is a material parameter that determines the extensibility of a single fiber. Fiber - tissue level: advance the fiber-level model into a tissue-level model by incorporating fiber distribution function and adding fiber density as the next set of material parameter. A multiscale mechanobiological model that incorporates inter-molecular cross-linking, fiber distribution and fiber density will be achieved for the description of tissue-level function. Specific Aim 2: Validation of the model using an integrated experimental - modeling approach. Tissue-level ECM mechanics: the tissue-level behavior of ECM network will be fully characterized using biaxial-tensile test. Elastin and collagen network will be isolated from aortic tissue and tested individually. Fiber distribution function: the fiber orientation information of elastin and collagen will be obtained using confocal microscopy and directly incorporated into the model. Fiber density and cross-linking: the content and crosslinking density of elastin and collagen will be measured biochemically through biological assay. Corresponding material parameters in the model will be determined from fits to the biaxial-tensile testing data. 1 PUBLIC HEALTH RELEVANCE: In this project, we seek to develop a multiscale predictive mechanobiology model for the study of extracellular matrix mechanics from a fundamental mechanics perspective coupled with critical biophysical input. The proposed work will be accomplished through two specific aims that couple modeling and experimental work for a complete model development and validation. Results from this research will provide clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. 1

描述(申请人提供)：随着目前非侵入性诊断技术的发展，临床上更准确地测量心血管疾病(CVD)的水平，一个重要的“平台科学”组成部分是更好地从机械上理解潜在的物理，如动脉壁的结构-功能力学。这些基本的认识大部分来自生物力学模型的开发和研究，这将为开发诊断学提供指导，而将这些诊断应用到临床环境中又为完善物理模型提供数据。在这个项目中，我们试图从基础力学的角度，结合关键的生物物理输入，建立细胞外基质(ECM)力学的多尺度预测力学模型，并提供ECM的生物力学完整性、生化成分稳定性和微结构之间的临床相关性关系。这种模型将使研究人员和临床医生能够探索基本机制，并帮助合理设计新的治疗心血管疾病的方法。具体目标1：建立ECM力学的多尺度预测性机械生物学模型。分子-纤维水平：采用基于统计力学的方法来确定单个纤维变形时的应变能变化。将采用自由连接链(FJC)模型来描述纤维在拉伸过程中可能的构型，从而描述其熵。分子间交联度是决定单一纤维延伸性的材料参数。纤维-组织层：通过引入纤维分布函数并添加纤维密度作为下一组材料参数，将纤维层模型推进到组织层模型。为了描述组织水平的功能，将得到一个包含分子间交联度、纤维分布和纤维密度的多尺度力学生物学模型。具体目标2：使用综合实验-建模方法对模型进行验证。组织水平的细胞外基质力学：细胞外基质网络的组织水平行为将通过双轴拉伸测试得到充分的表征。弹性蛋白和胶原网络将从主动脉组织中分离出来，并分别进行测试。纤维分布功能：利用共聚焦显微镜获得弹性蛋白和胶原的纤维取向信息，并直接融入模型中。纤维密度和交联度：弹性蛋白和胶原的含量和交联度将通过生物测定进行生化测定。模型中的相应材料参数将根据双向拉伸试验数据进行拟合确定。1 公共卫生相关性：在这个项目中，我们试图开发一个多尺度预测性机械生物学模型，用于从基础力学的角度结合关键的生物物理输入来研究细胞外基质力学。拟议的工作将通过两个具体目标来完成，这两个目标将建模和实验工作结合起来，以完成完整的模型开发和验证。本研究结果将提供ECM的生物力学完整性、生化成分稳定性和微结构之间的临床相关关系。1