Dr. Major's project is based on the recognition of the relevance of lipoprotein receptor Expression in macrophages as determinant of parameters of lipoprotein metabolism and atherogenesis. One important receptor expressed by the macrophage, and other cells, is the LDL receptor-related protein (LRP). To date, it has been impossible to evaluate independently the effect of LRP expression in macrophages in vivo because of the lack of viability by LRP homozygous deficient mice. Recently, through conditional inactivation of the LRP gene using the """"""""Cre-lox"""""""" system, evidence has been demonstrated by our collaborator, Dr. Joachim Herz (UT Southwestern), that liver LRP plays an important role in serum lipoprotein maintenance. This approach uses interferon induction of Cre recombinase to effectively delete gene segments that are flanked by specific sequences and results in complete LRP inactivation in the liver but may also result in complete or near complete inactivation of the LRP gene in the macrophage. For this reason, this proposal will explore this methodology to produce LRP deficient bone marrow to be used in transplantation studies where the recipient mice will be of strains susceptible to atherogenesis, such as C57BL/6 and the LDL receptor deficient mouse. With this approach, we will be able to create an in vivo model in which to study the effect of the LRP deficiency on macrophages in atherogenesis. This approach will result not only in very important observations on the biology of macrophage involvement in atherogenesis, but will provide a very valuable reagent, i.e., LRP negative macrophages, that can be used for binding and degradation Studies.
| Overton, Cheryl D; Yancey, Patricia G; Major, Amy S et al. (2007) Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ Res 100:670-7 |
| Su, Yan Ru; Ishiguro, Hiroyuki; Major, Amy S et al. (2003) Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. Mol Ther 8:576-83 |
| Major, Amy S; Fazio, Sergio; Linton, MacRae F (2002) B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol 22:1892-8 |
| Fazio, Sergio; Babaev, Vladimir R; Burleigh, Michael E et al. (2002) Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice. J Lipid Res 43:1602-9 |
| Major, A S; Dove, D E; Ishiguro, H et al. (2001) Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((-/-)) mice. Arterioscler Thromb Vasc Biol 21:1790-5 |
