CAREER: Vascular Stent Geometry Dictates Endothelial Cell Wound Healing and Phenotype

University Of Massachusetts Amherst, Amherst MA

Investigators

Abstract

Heart disease, including coronary artery disease, is the leading cause of death in both the USA and worldwide. Coronary artery disease is caused by blockage of one or more blood vessels of the heart by atherosclerosis, the build-up of plaques, which can lead to a heart attack. Stents are commonly used to treat coronary artery disease patients to prevent closure of the blood vessel. However, stents also carry clinical complications, often related to delayed healing of the wound that is created in the blood vessel after the stent is introduced. Endothelial cells, the cells lining the inside of blood vessels, play a key role in wound healing after a stent is introduced into the blood vessel. The goal of this Faculty Early Career Development Program (CAREER) project is to investigate how the blood flow environment around the individual stent struts affects endothelial cells so as to promote or prevent wound healing. Specifically, the project will study how expression of endothelial cell genes is affected by blood flow adjacent to the stent struts using a combined molecular biology and engineering approach. This advancement in knowledge will support the development of new treatment approaches to accelerate wound healing after introduction of the stent and decrease the complications associated with stents. Education and outreach activities will be integrated with the laboratory research. This award will also foster Science, Technology, Engineering and Math (STEM) opportunities at different educational levels, ranging from elementary school to undergraduate and graduate students. The overall research objective is to identify the genetic basis of endothelial cell wound healing in the fluid flow-environment surrounding a stent, a crucial step toward developing targeted therapies for patients after stenting. The hypothesis being investigated through this award is that the fluid flow environment around the stent strut impedes the normal wound healing process that is directed by endothelial cells. This will be supported through three research aims. In aim 1, the project will identify genes that prevent or promote wound healing in an in vitro environment that simulates stents. In aim 2, the project will develop a unique, high-throughput fluid flow system that will enable testing of multiple genes and flow conditions simultaneously, rapidly advancing the collection of results. Aim 3 will directly test the genes involved in endothelial cell-directed wound healing by using CRISPR/Cas9 mediated knock-out/knock-in to directly modify gene expression in endothelial cells to rescue directed cell migration and promote wound healing. The project also includes several educational objectives. University students will be exposed to the integration of engineering and medicine through courses, and extracurricular laboratory modules will contribute to increased awareness of interdisciplinary STEM careers. The award will also expand an existing pilot program in STEM for homeschooled elementary students, an often overlooked but rising student population in the US, in order to develop a complementary science curriculum with the goal to reach other homeschooling communities in the state and nationwide. 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.