Identifying Markers and Mechanisms of Atherosclerosis in Endothelial Cells Under Shear Stress Using High-Throughput Sequencing Data

Atherosclerotic cardiovascular disease is the top cause of mortality worldwide and has imposed a multi-billion-dollar burden on health care and economic growth. Vascular endothelial cells form the lining of the interior walls of blood vessels and are in direct contact with blood circulating through the vasculature. These endothelial cells exhibit physiological and pathophysiological responses to hemodynamic forces, including the formation of atherosclerotic lesions. The exact mechanisms of the dynamic response to hemodynamic forces by endothelial cells remain unclear. The advent of high-throughput sequencing technologies, along with the advent and growth of bioinformatics as a discipline, has brought with them an unprecedented ability to generate rich biological datasets and interrogate biological mechanisms on a systems level. In this dissertation, I take a bioinformatics and systems biology approach to understanding endothelial response to hemodynamic forces. In chapter 1, I provide an overview on atherosclerosis, endothelial cells, hemodynamic forces, and the in vitro techniques used to study them. In chapter 2, I describe a systems biology analysis of time series RNA-seq data that describes a dynamical map of endothelial response and a reconstruction of differences in transcriptional regulation across two different forms of hemodynamic forces. In chapter 3, I describe the study and characterization of several individual genes identified in my RNA-seq analysis, including LEENE, a long non-coding RNA whose relevance to endothelial homeostasis and shear stress was discovered through analysis of high-throughput sequencing data. In chapter 4, I describe a web suite constructed for the explicit purpose of data integration, along with integrated analysis of histone ChIP-seq data and RNA-seq data of endothelial cells exposed to shear stress. Chapter 5 concludes this dissertation with a discussion on the future directions and challenges of systems biology in application to atherosclerosis and endothelial cells