Godfrey S Getz
Research Summary / Selected Publications
Mice have relatively 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. We are addressing two issues in this connection.
Apolipoprotein E is a component of three plasma lipoproteins -- chylomicron remnants (CR) very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL). It is a ligand for many receptors -- the LDL receptors, the VLDL receptor and the LDL receptor related protein (LRP) and megalin (gp 330). It is thus closely involved in the clearance of many lipoproteins most notably CR and VLDL. The genetic removal of the apoE gene in mice results in profound hyperlipoproteinemia, affecting most remnants and VLDL.
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. We use site directed mutants of apoE to try and learn about this mechanism. Apolipoprotein A-I, the major apoprotein of HDL, 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. In man two major HDL subclasses exist, HDL2 and HDL3. High levels of HDL2 are particularly associated with atherosclerosis protection. We are attempting to use genetic modification of HDL to generate either HDL2 or HDL3 in elevated amounts in genetically engineered mice to directly test the hypothesis that HDL2 indeed 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 we are exploring apoE and LDL receptor deficient mice that are immune incompetent. We 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 our laboratory.
Finally apoE is a major product of the supporting cell of the central nervous system, the astrocyte. We are 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.
Mice have relatively 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. We are addressing two issues in this connection.
Apolipoprotein E is a component of three plasma lipoproteins -- chylomicron remnants (CR) very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL). It is a ligand for many receptors -- the LDL receptors, the VLDL receptor and the LDL receptor related protein (LRP) and megalin (gp 330). It is thus closely involved in the clearance of many lipoproteins most notably CR and VLDL. The genetic removal of the apoE gene in mice results in profound hyperlipoproteinemia, affecting most remnants and VLDL.
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. We use site directed mutants of apoE to try and learn about this mechanism. Apolipoprotein A-I, the major apoprotein of HDL, 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....
LaDu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, and Getz, GS. (2000) Lipoproteins in the central nervous system. Ann. NY Acad. Sci. 903:167.
LaDu, MJ, Shah J, Reardon CA, Getz GS, Bu G, Hu J, and Van Eldik L. (2000) Apolipoprotein E receptors mediate the effects of b-amyloid on astrocyte cultures. J. Biol. Chem. 275:33974.
Reardon CA and Getz GS. (2001) Mouse Models of Atherosclerosis. Curr. Opin. Lipidol. 12:167.
Reardon CA, Blachowicz L, White T, Cabana V, Wang Y, Lukens J, Bluestone J, and Getz GS. (2001) The effect of immune deficiency on lipoproteins and atherosclerosis in male apoprotein E deficient mice. Arterioscler. Thromb. Vasc. Biol. 21:1011.
Reardon CA, Kan H-Y, Cabana V, Blachowicz L, Lukens JR, Wu Q, Liadaki K, Getz GS, and Zannis VI. (2001) In vivo studies of HDL assembly and metabolism using adenovirus-mediated transfer of apoA-I mutants in apoA-I deficient mice. Biochemistry: 40(45):13670.
Reschly EJ, Sorci-Thomas MG, Davidson WS, Meredith SC, Reardon CA, Getz GS. Apolipoprotein A-I alpha helices 7 and 8 modulate high density lipoprotein subclass distribution. J Biol. Chem. Dec 14 prepubl. 2001.
LaDu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, and Getz, GS. (2000) Lipoproteins in the central nervous system. Ann. NY Acad. Sci. 903:167.
LaDu, MJ, Shah J, Reardon CA, Getz GS, Bu G, Hu J, and Van Eldik L. (2000) Apolipoprotein E receptors mediate the effects of b-amyloid on astrocyte cultures. J. Biol. Chem. 275:33974.
Reardon CA and Getz GS. (2001) Mouse Models of Atherosclerosis. Curr. Opin. Lipidol. 12:167.
Reardon CA, Blachowicz L, White T, Cabana V, Wang Y, Lukens J, Bluestone J, and Getz GS. (2001) The effect of immune deficiency on lipoproteins and atherosclerosis in male apoprotein E deficient mice. Arterioscler. Thromb. Vasc. Biol. 21:1011.
Reardon CA, Kan H-Y, Cabana V, Blachowicz L, Lukens JR, Wu Q, Liadaki K, Getz GS, and Zannis VI. (2001) In vivo studies of HDL assembly and metabolism using adenovirus-mediated transfer of apoA-I mutants in apoA-I deficient mice. Biochemistry: 40(45):13670.
