CAREER: Unraveling Mechanisms of Mechanical Degeneration in Elastin

职业生涯：揭示弹性蛋白机械变性的机制

• 批准号: 2145759
• 负责人: Anna Tarakanova
• 金额: $ 60.01万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2145759&HistoricalAwards=false
• 关键词: CAREER; Unraveling; Mechanisms; Mechanical; Degeneration

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.

该学院早期职业发展（CAREER）拨款将支持基础研究，以了解衰老和疾病中弹性蛋白发生的复杂变化。弹性蛋白是一种关键的结构蛋白，赋予生物组织弹性。 例如，由于弹性蛋白，皮肤、肺和动脉可以伸展和放松。 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理化应激源是相互关联的。许多这些压力源发生在纳米尺度。这种知识差距阻碍了新疗法的开发。 该研究计划的目标是开创对弹性组织机械退化的纳米级新见解。 具体来说，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开发旨在维持弹性组织生物力学功能的新疗法，以预防或延缓衰老和疾病的并发症。该研究项目还将通过多样化的研究经验和研究博览会中的女性 STEM 前沿活动，吸引和支持本科生和研究生，特别是来自代表性不足群体的学生。 这将催生新的跨学科课程，并促进新的本地计算生物物理学家网络。该研究项目将为健康和退化的弹性蛋白建立新的高保真建模框架，作为解决病理理化应激源对纳米尺度力学影响的工具，并确定导致弹性组织机械功能丧失的特定驱动因素。 PI 最近开发了弹性蛋白前体弹性蛋白原的第一个全原子模型，为系统地独立和组合地探索有害刺激奠定了基础。这项研究将建立健康和退化弹性蛋白的多尺度数字孪生，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）如何导致结构变化，独立和协同影响机械功能，并紧密破坏 将水合水动力学与非结构化弹性蛋白耦合。这项工作将提供：1）经过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、分层无序分子系统； 2）对水合水在此类系统中的作用的基本了解； 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制理解； 4) 吸引和留住多元化学生的教育计划。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Changes in elastin structure and extensibility induced by hypercalcemia and hyperglycemia

• DOI: 10.1016/j.actbio.2022.03.041
• 发表时间: 2023-05-12
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Yang，Chengeng;Weiss，Anthony S.;Tarakanova，Anna
• 通讯作者: Tarakanova，Anna