Multiscale Effects of Aging on Elastic Arterial Tissue Mechanics

项目摘要 弹性蛋白在脊椎动物中进化，以支持封闭的脉动循环系统， 增选以支持在各种器官中的可逆延伸，例如肺、内脏和皮肤。它 具有显著的弹性特性，在大应变之后以最小的能量损失支持反冲 数百万到数十亿次的拉伸-回弹循环而不发生故障。尽管其重要的生物学和 机械功能，整个弹性蛋白前体单体（原弹性蛋白）的结构和所得的弹性蛋白的结构。 聚合物一直是未知的，阻碍了对弹性蛋白功能的全面分子理解， 和疾病 我们先前的研究已经确定了原弹性蛋白的形状，使用分子建模的整个 多肽链，显示出匹配的整体形状，以小角度X射线散射数据，并实现 结构的原子分辨率。我们发现，该模型正确地识别了结构变化， 与关键分子位点的突变相关，并发现了它们的影响机制， 结构到功能。此外，我们还发现，弹性纤维网络随着时间的推移逐渐变硬， 非酶糖化。该提案的总体目标是利用这些开创性的 了解动脉弹性蛋白功能的结构和分子决定因素的初步结果 组织在健康和老化，使用跨学科的实验建模方法，采用 分子和多尺度建模、生化表征、多尺度生物力学测试，以及 光学成像在三个研究目标：（1）确定推定的老化相关损伤部位， 在驱动弹性蛋白二聚体的机械变化的过程之间建立耦合机制， 天然酶促交联弹性蛋白的最小代表性分子单位;（2）确定作用 天然酶和非酶（老化相关的病理性）交联在调节弹性纤维 力学通过弹性纤维的介观模型;和（3）解决如何纤维力学和 微尺度冲击弹性纤维网络结构和力学的交联倾向 在老化过程中。 这项研究将建立一个框架，广泛研究多尺度结构， 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 和弹性组织中的机械功能。通过这些研究获得的见解将有一个翻译 对发展心血管疾病预防、诊断和修复干预措施的影响， 其他与年龄有关的疾病。 1

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