CAREER: Unraveling Mechanisms of Mechanical Degeneration in Elastin

University Of Connecticut, Storrs CT

Investigators

Abstract

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.