Laboratory Research

The Marc and Ruti Bell Vascular Biology and Disease Program

Marc and Ruti Bell Vascular Biology Program Laboratory

The foundation of many of today's clinical treatments and diagnostic approaches regarding heart disease have come from basic research. Headed by Dr. Edward Fisher, this rapidly expanding program utilizes state-of-the-art techniques to explore the biology of diseases of the vasculature. Dr. Fisher's team focuses on the regulation of the lipid risk factors for atherosclerotic heart disease.

As you read in the Lipids and Your Health section, it becomes evident that there is a "bad" and "good" cholesterol. The "bad" cholesterol represents the cholesterol that is being delivered to the cells of your body, particularly to the cells in the wall of your coronary arteries. This cholesterol is carried on lipoprotein particles that have apolipoprotein B (apoB) as a major component. ApoB is made in the liver and intestine, where it is used to package the fats (including cholesterol and triglycerides) either made in liver or absorbed from the diet in the intestine. These "packages", or lipoprotein particles, then enter the bloodstream from the liver are called VLDL and deliver their fatty cargo to cells throughout the body.


Basic Pathways in LDL Regulation

Unfortunately, the coronary artery is susceptible to these apoB-containing lipoprotein particles because they can get trapped in the artery wall, resulting in the cholesterol build-up that eventually forms plaques. VLDL can become even worse when it gets converted to LDL.

Dr. Fisher's laboratory has recently focused on the assembly process for VLDL in liver cells and have discovered, for example, that the amount of VLDL produced depends on how much apoB is degraded in the liver cell. Thus, a therapeutic strategy to lower the blood levels of "bad" cholesterol, particularly for those patients either not responsive enough or tolerant to existing cholesterol or triglyceride-lowering medications, would be to develop a drug that increases apoB degradation in the liver. In fact, based on discoveries such as the type made in Dr. Fisher's laboratories, the pharmaceutical industry is currently pursuing such an approach.

To give an illustration of the tools used in this aspect of Dr. Fisher's research, please examine the picture of a liver cell shown below.

>"Bad" Lipoprotein Assembly in a Liver Cell

Note the green color- these are apoB molecules that have associated with cholesterol and triglycerides in the liver cell to form VLDL particles. Using recombinant DNA technology, an apoB molecule a green fluorescent protein "tag" was incorporated. By using a microscope with a special light source, we can now easily follow apoB around the liver cell to more conveniently investigate whether and where in the cell different treatments might affect VLDL assembly and secretion.

Other projects in the laboratory include the study of animal models of atherosclerosis to determine the genes that are important for plaque growth and regression. This type of information may ultimately be useful for clinical diagnostic and therapeutic purposes.