The research in my laboratory is centered on developing an understanding of the genetic basis of atherosclerosis. This common but complex multifactorial disease is the leading cause of death in modern societies. We use gene targeting experiments in mice to introduce specific alterations in various genes that are involved in lipid metabolism or in the maintenance of vascular integrity. Using the spontaneous atherosclerosis developing in apolipoprotein E-deficient mice as a basis, we investigate how combinations of genetic factors modulate the development of vascular lesions and/or how specific environmental factors such as diet and drug treatment interact with the gene defects. The mouse mutants will soon be used in a genome-wide screen to identify genes that respond when cardiovascular homeostatic mechanisms are altered.