Notch mediated mechanisms of mammalian cerebral angiogenesis
Initial Award Abstract
Smoking dramatically increases the risk of cardiovascular disease, including various forms of cerebrovascular disease. Estimates suggest a smoker’s risk of developing cerebrovascular disease is 1.5 to 3 times greater than that of a nonsmoker. Cerebrovascular disease, including stroke and arterial-venous malformations, often lead to devastating neurological dysfunction. Indeed, 50% of survivors of cerebrovascular disease experience neurological deficit, half of which require chronic care. In the United Stated alone, over 15,000 deaths per year are directly attributed to smoking-induced cerebrovascular disease; however, the mechanisms that trigger cerebrovascular disease remain poorly understood. |
The vasculature plays a principal role in health and disease, by providing a vital platform for perfusion and nutrition of tissues. Smoking has been shown to reduce the ability of the blood to transport oxygen, thereby adversely affecting tissue health. In particular, the tissue lining blood vessels - vascular endothelium - is damaged by components of cigarette smoke. Herein, we propose experiments to investigate genetic mechanisms enacted within the vascular endothelium of the brain. Our goal is to understand the mechanisms that promote the growth of new and existing blood vessels within the brain.
We propose an analysis of the dynamic remodeling of blood vessels within the brain shortly after birth. While many blood vessels have already been established by birth, the organization and ultimate function(s) of these vessels is not yet mature. In particular, we will study the role of a specific gene (called Notch) during this maturation phase for blood vessels within the brain. By altering Notch gene function specifically in cells (vascular endothelial cells) lining these blood vessels, we hope to understand the normal function of the Notch gene product in the brain vasculature. As our long-term interests lie in the development, function, and disease state of human blood vessels within the brain, we use another mammal - the mouse - as an appropriate and applicable experimental model system to inform on events relevant to human biology. The success of these studies will provide conceptual advances toward understanding the normal course of blood vessel formation in the brain and fostering therapeutic advances for cerebrovascular disease.