I have a long-standing interest in intracellular cholesterol metabolism that dates back to my days as a graduate student and postdoctoral fellow at the Wake Forest University School of Medicine (Molecular and Cellular Pathobiology) and Dartmouth Medical School (Biochemistry), respectively. Several years ago my laboratory showed (J Biol Chem 2000;275:38104-10) that accumulation of cholesterol in lysosomes down-regulates an enzyme (acid sphingomyelinase) that appears to play an important role in apoptosis, a form of programmed cell death. The ability of cells to undergo apoptosis at appropriate times is crucial in the developmental process and the elimination of potentially cancerous cells. Therefore, my laboratory is currently conducting studies aimed at elucidating the molecular mechanism(s) responsible for the cholesterol-mediated regulation of lysosomal enzymes involved in apoptosis. In addition, we are also actively developing cell culture and animal models that will allow us to identify potentially novel proteins that play pivotal roles in the regulation and execution of cell death pathways. The overarching goal of these studies is to expand our knowledge and understanding of the fundamental mechanisms that link intracellular cholesterol metabolism with programmed cell death and thereby aid in the development of potentially novel therapeutics for the treatment and/or prevention of diseases such as cancer and atherosclerosis (hardening of the arteries).