Project 172001

Diseases of the cardiovascular system, such as coronary heart disease and stroke due to atherosclerosis, are known to start in the vascular endothelium. This research laboratory has a long-term interest in understanding how endothelial genes are regulated in health and disease. We argue that we need to understand how genes are expressed in the endothelial cells of the body and how these pathways become abnormal in disease. What makes an endothelial gene turn off in diseased human blood vessels? Classically the nucleus has been viewed as the key regulator of gene expression. Yet all cells have the same DNA. Why do endothelial cells express only certain genes in healthy tissue? In disease many of these genes turn off. Why does the nucleus get affected? These processes are chromosome-based or chromatin-based, and are also called epigenetic processes. What we inherit from our parents, or what one cell passes on two cells when it divides, represents the "nature" side of the equation. These processes are influenced by the environment. This represents the "nurture" side of the equation. Whatever our cells sense in their external world interacts with genetic material in the nucleus to influence gene expression. Epigenetics is broadly defined as the mechanisms that control gene expression that do not involve the DNA sequence per se. We are among the first to study these concepts in the cardiovascular sciences. We believe that the principles we uncover in endothelial cells will teach us about blood vessels gene regulation in general. Our understanding of these newer concepts offers the hope of innovative approaches to preventing and treating the underlying problem in diseased blood vessels of patients. We anticipate findings that will provide important new insight into how genes are turned on and off in disease.