Multiscale Effects of Aging on Elastic Arterial Tissue Mechanics

衰老对弹性动脉组织力学的多尺度影响

• 批准号: 10811244
• 负责人: Anna Tarakanova
• 金额: $ 28.03万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10811244
• 关键词: Adsorption; Affect; Age; Aging; Architecture; Arteries; Automobile Driving; Behavior; Binding; Biochemical; Biological; Biological Aging; Biological Assay; Blood Circulation; Calcium; Calibration; Cardiovascular system; Circular Dichroism; Collagen; Complex; Computer Models; Connective Tissue; Coupled; Coupling; Data; Development; Diagnosis; Diagnostic; Disease; Elastic Fiber; Elastic Tissue; Elasticity; Elastin; Environment; Experimental Models; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Fiber; Frustration; Functional disorder; Glucose; Goals; Grain; Health; Heterogeneity; Human; Hydration status; Impairment; Intervention; Investigation; Kinetics; Knowledge; Length; Link; Location; Longevity; Lung; Mass Spectrum Analysis; Mechanics; Methods; Modeling; Modification; Molecular; Mutation; Nature; Organ; Pathologic; Polymers; Polysaccharides; Post-Translational Protein Processing; Process; Property; Proteins; Reproducibility; Research; Resolution; Roentgen Rays; Role; Shapes; Site; Skin; Spectrum Analysis; Stretching; Structural Protein; Structure; Testing; Thermodynamics; Tissues; Tropoelastin; Vertebrates; Viscera; Water; Work; age effect; age related; aged; biomechanical test; calcification; crosslink; density; dimer; experimental study; glycation; insight; mechanical drive; molecular modeling; molecular scale; molecular site; monomer; multi-scale modeling; multiphoton microscopy; network architecture; network models; optical imaging; polypeptide; single molecule; stressor; translational impact

Project Summary Elastin evolved in vertebrates to support a closed, pulsatile circulatory system, and was subsequently co-opted to support reversible extension in a variety of organs, such as the lungs, viscera, and skin. It has remarkable elastic properties supporting recoil following large strains with minimal loss of energy over millions to billions of stretch-recoil cycles without failure. Despite its important biological and mechanical function, the structure of the entire elastin precursor monomer (tropoelastin) and the resulting polymer has been unknown, hampering full molecular understanding of elastin function in both health and disease. Our prior research has determined the shape of tropoelastin using molecular modeling of the entire polypeptide chain, showing a matching overall shape to small-angle X-ray scattering data, and achieved atomic resolution of the structure. We showed that the model correctly identified structural changes associated with mutations in key molecular sites and discovered their mechanisms of impact, linking structure to function. Furthermore, we showed that the elastic fiber network stiffens progressively with non-enzymatic glycation. The overall goal of this proposal is to leverage these groundbreaking preliminary results to understand the structural and molecular determinants of elastin function in arterial tissue in health and upon aging, using an interdisciplinary experimental-modeling approach, employing molecular and multiscale modeling, biochemical characterization, multiscale biomechanical testing, and optical imaging within three research aims: (1) identify putative aging-associated damage sites and establish coupling mechanisms between processes driving mechanical changes in elastin dimers, the smallest representative molecular unit of native enzymatically crosslinked elastin; (2) determine the role of native enzymatic and non-enzymatic (aging-linked pathological) crosslinks in modulating elastic fiber mechanics via a mesoscale model of elastic fibers; and (3) resolve how fiber mechanics and the propensity of crosslinking at the microscale impact elastic fiber network architecture and mechanics during aging. The proposed research will establish a framework to broadly investigate the multiscale structure and multifactorial modifications associated with aging and age-related diseases that affect structural change and mechanical function in elastic tissue. Insights gained through these studies will have a translational impact on the development of preventative, diagnostic and reparative interventions to cardiovascular and other age-related diseases. 1

项目概要 弹性蛋白在脊椎动物中进化来支持封闭的脉动循环系统，随后被 共同选择支持多种器官的可逆延伸，例如肺、内脏和皮肤。它 具有卓越的弹性特性，支持大应变后的反冲，同时能量损失最小 超过数百万至数十亿次拉伸-反冲循环而不会出现故障。尽管它具有重要的生物学和 机械功能、整个弹性蛋白前体单体（原弹性蛋白）的结构以及所得的 聚合物一直是未知的，阻碍了对弹性蛋白在健康和健康中的功能的全面分子理解 和疾病。 我们之前的研究已经使用整个分子模型确定了原弹性蛋白的形状 多肽链，显示出与小角 X 射线散射数据相匹配的整体形状，并实现了 结构的原子分辨率。我们证明该模型正确识别了结构变化 与关键分子位点的突变相关，并发现了它们的影响机制，将 结构到功能。此外，我们表明弹性纤维网络逐渐变硬 非酶糖化。该提案的总体目标是利用这些突破性的 初步结果了解动脉弹性蛋白功能的结构和分子决定因素 使用跨学科的实验建模方法，采用健康和衰老时的组织 分子和多尺度建模、生化表征、多尺度生物力学测试以及 光学成像的三个研究目标是：（1）识别假定的与衰老相关的损伤部位和 建立驱动弹性蛋白二聚体机械变化的过程之间的耦合机制， 天然酶交联弹性蛋白的最小代表性分子单元； (2)确定角色 天然酶促和非酶促（衰老相关病理性）交联在调节弹性纤维中的作用 通过弹性纤维的介观模型进行力学； (3)解决纤维力学和 微尺度冲击弹性纤维网络结构和力学的交联倾向 老化期间。 拟议的研究将建立一个框架来广泛研究多尺度结构和 与影响结构变化的衰老和年龄相关疾病相关的多因素修饰 和弹性组织的机械功能。通过这些研究获得的见解将具有转化意义 对心血管疾病预防、诊断和修复干预措施发展的影响 其他与年龄有关的疾病。 1