Lipid Metabolism, Atherosclerosis, Diabetes, Obesity, Vascular Biology
Our research program focuses on three specific areas relating cholesterol metabolism with individual susceptibility for coronary heart disease.
Particular emphasis is placed on the genetic factors that are important for regulation of cholesterol transport and in the maintenance of cell functions in the arterial wall.
One area of research uses induced mutant mice (transgenic and knockout mice) to determine the role of lipolytic enzymes and intestinal cell surface transporters in mediating dietary fat and cholesterol absorption through the gastrointestinal tract.
Mutant mice generated from these studies are also being used as an animal model to explore the potential of gene therapy as treatment for nutrient alabsorption due to pancreatic insufficiency. The mechanism by which the lipolytic enzymes and transport proteins mediates cholesterol absorption is being explored using protein chemistry and site specific mutagenesis approaches.
The second area of research uses tissue cell culture and transgenic mice to identify the interactive effects between diet and genetic factors in the maintenance of plasma cholesterol level and determination of atherosclerosis risk.
The current emphasis is focused on the role of cholesterol esterase, apolipoprotein (apo) E, LDL receptor, HMG-CoA reductase, and other hepatic lipoprotein receptors in determining individual susceptibility to diet-induced hyperlipidemia and atherosclerosis.
Major effort in the laboratory is also spent on the third project, which is to determine the molecular and cellular events in the arterial wall in response to injury, such as those observed in human subjects undergoing balloon angioplasty.
A mouse model of arterial injury has been established in the laboratory for this purpose. This model will be used to explore cell signaling mechanisms of arterial smooth muscle cell hyperplasia. Genetic factors that may contribute to or limit the vascular cell responses after injury will be identified by genetic approaches.
Particular emphasis is placed on testing the hypothesis that apoE has cytostatic functions in the vessel wall, limiting arterial smooth muscle cell hyperplasia after injury, and that apoE gene transfer to the vasculature may be a potential therapeutic treatment to reduce the risk of restenosis after balloon angioplasty.