Mice have recently become suitable models for the study of atherosclerosis, because of the availability of genetically engineered mice that spontaneously develop atherosclerosis. These are mice with disruption of the apoE gene and the LDL receptor gene. Both apolipoprotein E and apolipoprotein A-I will attenuate atherogenesis.

The local expression of apoE in the vessel wall is effective in this protective effort. But the precise mechanism by which this works is not clear. Dr. Getz and his lab use site directed mutants of apoE to learn about this mechanism. Apolipoprotein A-I is thought to protect against atherosclerosis by facilitating the movement of cholesterol from the blood vessel wall to the liver where it is excreted in the bile. High levels of HDL2 are particularly associated with atherosclerosis protection. Dr. Getz is attempting to use genetic modification of HDL to generate either HDL2 or HDL3 in elevated amounts in genetically engineered mice to test the hypothesis that HDL2 is more effective in atherosclerosis protection. This involves understanding how the sequence of apoA-I controls the kinds of HDL that are formed, which is now a major focus.

Atherosclerosis is an inflammatory disease involving cells of innate and adoptive immunity. To study the role of the cells and biochemical mediators of the immune system Dr. Getz is exploring apoE and LDL receptor deficient mice that are immune incompetent. Dr. Gatz and his lab find that immunological mediators affect lipoprotein level and composition and also differentially affect atherosclerosis in different vascular beds – i.e. as different arterial sites. The basis for this site specific effect of the immune system on atherosclerosis is a major question for the laboratory.

Finally apoE is a major product of the supporting cell of the central nervous system, the astrocyte. Dr. Getz is intensively studying the nature of lipoproteins produced by astrocytes expressing apoE3 or apoE4, two major isoforms of apoE found in the blood tissues. ApoE4 is a major risk factor for Alzheimer’s disease, so the kinds of lipoproteins produced by astrocytes could have a major impact on the nutrition and differentiation of neurons.