Tissue engineering provides a strategy for developing better biomaterials for use in congenital heart surgery.
Results of our clinical trials evaluating the use of tissue engineered vascular grafts (TEVGs) in congenital heart
surgery have demonstrated the growth capacity of the TEVG making it the first man made graft with growth
potential. However, results of these trials have also revealed that stenosis is the most common graft-related
complication and the principle hurdle preventing its widespread clinical use. Recently, we have identified a novel
immune-regulatory protein encoded by the LYST gene. Mutations of the LYST gene dramatically reduce the
incidence of TEVG stenosis in murine models. In this proposal, we will investigate the cellular and molecular
mechanisms underlying the formation of LYST-mediated TEVG stenosis. We will use a on-demand inducible
LYST-mutant mouse to determine the critical temporal factors underling this process. Next, we will use a
conditional LYST-mutant model to elucidate the roles of macrophages and determine the critical cell type(s)
responsible for driving LYST-mediated TEVG stenosis. Finally, we will evaluate the role of extracellular vesicle-
dependent intercellular signaling on the formation of LYST-mediated TEVG stenosis. Successful completion of
these studies would open the door to rationally designing strategies to inhibit the formation of TEVG stenosis
based on modulating LYST function. The development of an improved TEVG with growth capacity has the
potential to improve outcomes for children born with congenital heart disease.