Grant: Operating Grant

Leading causes of mortality include cardiovascular disease, stroke and cancer. What all these diseases have in common is that vascular endothelial cells that cover the lining of blood vessels directly participate in the generation and /or progression of these diseases. Damage or dysfunction of cardiovascular and brain vascular endothelial cells is the major cause of heart disease and stroke respectively. While growth of endothelial cells to generate new blood vessels that vascularize tumors is the route of cancer metastasis. A major obstacle in developing effective therapies for these diseases is the lack of knowledge of how endothelial cells are different from other cell types, how in various organs endothelial cells differ from each other, and how endothelial cells respond to injuries. This knowledge is essential for determining why endothelial cells of specific organs, but not all vascular endothelial cells become susceptible to dysfunction in these diseases. We propose to determine the molecular mechanisms that are invoked in response to injuries such as irradiation and hypoxia. We have developed a system to target expression of desired genes in endothelial cells of specific organs and we will use this system to explore the response of endothelial cells of target organs to injury in transgenic mice in addition to cell culture. These studies will provide necessary information to develop therapeutic approaches to inhibit processes that are activated in endothelial cells in response to injury and finally target the endothelial cells of each organ specifically for future effective therapies for vascular diseases.