CAREER: Unraveling Mechanisms of Mechanical Degeneration in Elastin

该学院早期职业发展（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关键结构蛋白。 例如，皮肤，肺和动脉可以伸展和放松，这要归功于弹性蛋白。 在衰老或疾病期间，弹性蛋白的问题会导致组织变性，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生理化学应激源是联系在一起的。许多这些压力源发生在纳米级。这种知识上的差距阻碍了新疗法的开发。 这项研究计划的目的是开拓新的纳米尺度洞察弹性组织的机械变性。 具体来说，这项工作将使用计算机建模框架，将从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旨在维持弹性组织的生物力学功能以预防或延迟衰老和疾病并发症的新疗法。该研究计划还将参与和支持本科生和研究生，特别是来自代表性不足的群体，通过不同的研究经验和妇女在STEM前沿研究博览会。 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。该研究计划将建立一个新的高保真建模框架，为健康和退化的弹性蛋白作为一种工具，以解决在纳米尺度上的病理物理化学应力对力学的影响，并确定特定的驱动程序的弹性组织的机械功能的损失。PI最近开发的弹性蛋白前体原弹性蛋白的第一个全原子模型为独立和组合地系统探测有害刺激奠定了基础。这项研究将建立健康和变性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-特别是糖化和非酶交联，异位钙化，酶促蛋白水解，氧化损伤，外消旋化，脂质过氧化和氨甲酰化-如何促进结构变化，独立和合作地影响机械功能，并破坏与非结构化弹性蛋白紧密耦合的水合水动力学。这项工作将提供：1）验证的计算工具来表征弹性蛋白的多尺度结构和机械响应，并应用于其他异质、分层无序的分子系统; 2）对水合水在此类系统中的作用的基本见解; 3）对衰老和疾病期间弹性蛋白功能丧失的可能具体途径的机械理解;该奖项反映了NSF的法定使命，并通过使用基金会的智力价值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.