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.