CAREER: Unraveling Mechanisms of Mechanical Degeneration in Elastin

这笔学院早期职业发展(Career)补助金将支持基础研究，以了解在衰老和疾病中发生的弹性蛋白的复杂变化。弹性蛋白是赋予生物组织弹性的一种关键结构蛋白。例如，皮肤、肺和动脉可以在弹性蛋白的作用下伸展和放松。在衰老或疾病期间，弹性蛋白的问题会导致组织退化，从而抑制正常功能。这是一个具有挑战性的研究问题，因为可能导致退化的物理化学应激源是相互关联的。其中许多应激源都发生在纳米尺度上。这种知识上的差距阻碍了新疗法的开发。这项研究计划的目标是开创对弹性组织机械性退化的新的纳米级洞察力。具体地说，这项工作将使用计算机建模框架，该框架将根据测量的实验结果进行校准。了解弹性蛋白损伤的各种来源可能有助于新的治疗方法，旨在维持弹性组织的生物力学功能，以预防或延缓衰老和疾病的并发症。该研究计划还将通过不同的研究经验和STEM研究前沿的女性研究博览会，吸引和支持本科生和研究生，特别是来自代表不足的群体的学生。这将导致一个新的跨学科课程，并促进一个新的计算生物物理学家的本地网络。本研究计划将为健康和退行性弹性蛋白建立一个新的高保真建模框架，作为在纳米尺度上解决病理性物理化学应激源对力学的影响的工具，并确定导致弹性组织机械功能丧失的特定驱动因素。PI最近建立了第一个弹性蛋白前体原弹性蛋白的全原子模型，为系统地独立和联合探测有害刺激奠定了基础。这项研究将建立一个健康和退化的弹性蛋白的多尺度数字双胞胎，以阐明关键的物理化学应激源--特别是糖基化和非酶交联、异位钙化、酶蛋白分解、氧化损伤、外消旋化、脂质过氧化和氨基甲酰化--如何促进结构变化，独立和协同地影响机械功能，并与非结构化弹性蛋白扰乱紧密耦合的水合水动力学。这项工作将提供：1)经过验证的计算工具，以表征弹性蛋白的多尺度结构和机械响应，并应用于其他不同的、分层的无序分子系统；2)对水合水在此类系统中的作用的基本洞察；3)从机械上了解在衰老和疾病期间弹性蛋白功能丧失的可能特定路径；以及4)一个吸引和留住不同学生的教育计划。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) grant will support fundamental research to understand complex changes to elastin that occur in aging and disease. Elastin is a key structural protein that gives biological tissues their elasticity. For example, skin, lungs, and arteries can stretch and relax thanks to elastin. During aging or disease, problems with elastin can cause tissue degeneration, which inhibits normal function. This is a challenging problem to study because the physiochemical stressors that can lead to degeneration are linked together. Many of these stressors occur at the nanoscale. This gap in knowledge prevents new therapies from being developed. The objective of this research program is to pioneer novel nanoscale insight into mechanical degeneration of elastic tissues. Specifically, this work will use a computer modeling framework, which will be calibrated from measured experimental results. Understanding the various sources of damage to elastin may facilitate new therapies aimed at maintaining biomechanical function of elastic tissues to prevent or delay complications in aging and disease. The research program will also engage and support undergraduate and graduate students, especially from underrepresented groups, through diverse research experiences and the Women in STEM Frontiers in Research Expo. This will lead to a new interdisciplinary curriculum and promote a new local network of computational biophysicists.This research program will establish a new high-fidelity modeling framework for healthy and degenerated elastin as a tool to resolve the impacts of pathological physicochemical stressors on mechanics at the nanoscale and identify specific drivers to the loss of mechanical function of elastic tissues. The PI’s recent development of the first all-atom model of the elastin precursor tropoelastin lays a foundation for systematically probing deleterious stimuli independently and in combination. This research will establish a multiscale digital twin of healthy and degenerated elastin to elucidate how key physicochemical stressors, – specifically glycation and non-enzymatic crosslinking, ectopic calcification, enzymatic proteolysis, oxidative damage, racemization, lipid peroxidation, and carbamylation – contribute to structural change, impact mechanical function independently and cooperatively, and disrupt tightly coupled hydration water dynamics with unstructured elastin. This work will provide: 1) validated computational tools to characterize the multiscale structure and mechanical response of elastin, with applications to other heterogeneous, hierarchical disordered molecular systems; 2) fundamental insight into the role of hydration water in such systems; 3) mechanistic understanding of likely specific paths to loss of function in elastin during aging and disease; and 4) an educational program to engage and retain diverse students.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.