This NSF Faculty Early Career Development (CAREER) Program award will study the mechanisms by which the cells of the heart valve can change from a stable, endothelial state into a mobile, mesenchymal state, via a process termed endothelial-mesenchymal transformation (EndoMT). Heart valves are sophisticated structures that function in a complex mechanical environment, directing flow by opening and closing more than three billion times during a normal human lifetime. The valve is unique within the circulatory system in its ability to undergo EndoMT, a process that is crucial to the growing embryo, and also to how the valve adapts to the mechanical environment to maintain itself and to respond to injury. The award will support fundamental research into the mechanobiology of EndoMT to determine how friction of the blood, flexing of the valve and other mechanical effects change the biological response of the living tissue. Broader impacts include the development of new treatments for valve disease and improving tissue engineering strategies to build new heart valves. The educational component is centered on exposing underrepresented high-school seniors to multidisciplinary engineering research at a week-long summer camp. The camp will integrate theory and practice of mechanobiology and artificial tissue fabrication, and is planned to increase student awareness and interest in science and engineering.
The research objective of this award is to advance the understanding of the role of cellular structure, architecture and mechanical milieu in the regulation of EndoMT. The following objectives are to be undertaken to understand this phenomenon: (I) Engineer a microfabricated system that applies defined strain, fluid flow and substrate stiffnesses to valve endothelial cells. (II) Examine the EndoMT process in these cells under mechanical and architectural regimes that mimic early development, homeostasis, growth, injury and disease using live imaging. (III) Examine the mechanoregulatory genes that control the EndoMT process via pharmacological inhibition or gene deletion. This award will provide important insights into the mechanoregulation of cellular phenotype and plasticity in the cardiac valve, and the key signaling molecules that control these processes.
