The overall goal of this program project is to use transgenic and knockout mice to better understand selected aspects of the complex processes of lipoprotein metabolism and atherogenesis. The ability to manipulate the germ line of the mouse enables us to ask very specific questions about how relevant genes function in the body. It is also possible to reconstruct the mouse lipoprotein system by these genetic tools to mimic human dyslipoproteinemias and even to enhance atherosclerosis susceptibility. One example is our recent development of the apo E knockout mouse which accumulates high levels of cholesterol ester enriched lipoprotein remnants in plasma and develops extensive fibroproliferative human-like atherosclerotic lesions even on a low fat low cholesterol diet. Five projects and two cores are proposed. The projects entail studying: 1) cholesterol ester transfer protein gene regulation and function (Tall) 2) Lipoprotein lipase in lipoprotein metabolism, energy homeostasis, and atherogenesis (Breslow) 3) phospholipid transfer protein in lipoprotein metabolism and atherogenesis (Jiang) 4) altered macrophage phospholipid metabolism as a basis for foam cell necrosis (Tabas) 5) macrophage apo E gene expression and the ole of apo E in macrophage cholesterol metabolism as well as other macrophage functions which might play a role in atherogenesis (Smith). All of these projects make extensive use of the proposed transgenic core facility which will allow for the creation of new transgenic and knockout mice, crossbreeding genetically altered as well as naturally mutant mice, and embryo freezing. These projects will provide important new information about the genetic regulation of VLDL and HDL metabolism by lipases and lipid transfer proteins and how the genetic regulation of VLDL and HDL metabolism by lipases and lipid transfer proteins and how this might influence atherosclerosis susceptibility. They will also provide insight into aspects of macrophage biology such as macrophage LPL, apo E, and phospholipid metabolism which may be relevant to the formation and progression of atherosclerotic lesions. Overall, these studies are likely to contribute important new mechanistic information relevant to human dyslipidemia and atherogenesis.
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