Dynamic Role of Hyaluronan in Ventricular Remodeling

Project Abstract The extracellular matrix (ECM) provides structural and functional support for the myocardium; however, heart failure alters the composition of the ECM. The ECM is composed of a number of proteins, lipids, and saccharides, yet their function is largely unknown. We found that one of the most abundant components of the ECM, hyaluronan (HA), accumulates following myocardial infarction; however, the role of HA following during infarct- induced heart failure is not known. Fibroblasts are a major cell type involved in ventricular remodeling. Once activated, fibroblasts proliferate and produce ECM components, such as collagen and HA. These events are associated with acute scar formation and chronic ventricular remodeling. In this project, I will explore the extent to which fibroblast-derived HA impacts the extracellular matrix. Specifically, I will study fibroblasts collagen secretion when HA metabolism is manipulated. Additionally, I will examine the extent to which fibroblast-derived HA contributes to acute scar formation post-MI. Finally, I will determine the extent to which fibroblast-derived hyaluronan contributes to chronic ventricular remodeling. We contend that acute increases in HA accumulation are required for scar formation following acute MI; however, the persistent, excessive production of HA provokes fibrosis beyond the initial scar. Hence, we predict that HA has a dynamic role following infarct-induced heart failure: beneficial early and maladaptive late. Taken together, these studies will provide novel insight into the role of HA in collagen secretion, acure scar formation, and chronic fibrosis. With this fundamental knowledge, we can, in future studies, explore therapeutic approaches. Regardless of the specific findings of this research plan, this fellowship will serve as an excellent vehicle to enhance my training so I can eventually become an independent scientist leading my own research laboratory. The combination of the experimental plan, experimental tools, my sponsor, the environment, advanced coursework, and professional development opportunities creates a high likelihood for me to realize my eventual goals and contribute significantly to the literature in the process.