The theme of the current PPG is the study of lipoproteins and atherosclerosis in induced mutant mice, with the main focus on understand apolipoprotein and lipoprotein processing gene function through the use of various transgenic and knockout models. Scientific knowledge gathered in the last 5 years now makes it possible to ask deep questions related to genes and pathways controlling atherosclerotic lesion formation and progression, macrophage cholesterol and phospholipid metabolism, cholesterol regulation of gene transcription, and the particular role of HDL and the lipid transfer protein proteins that regulate HDL levels in atherogenesis. We believe that this new knowledge will allow the achievement of the theme of the proposed PPG, which is the identification of new genes and pathways involved in cholesterol homeostasis and atherosclerosis. The investigators involved in the proposed PPG are on the faculties of two of New York's leading research universities, Rockefeller and Columbia. The PI, Drs. Breslow, and the co- PI, Dr. Tall, metabolism and atherogenesis. They are joined in this effort by 2 very talented mid-career faculty, Drs. Tabas and Smith, who both share interests in macrophage biology and the role of the macrophage in atherosclerosis. Three cores are proposed: a continuation of the transgenic and knockout mouse core headed by Dr. Walsh, a new gene expression profiling core headed by Dr. Swergold, and an administrative core. The projects entail studying: 1) atherosclerosis susceptibility genes in the mouse (Breslow-RU), 2) macrophage death and lipid metabolism in atherosclerosis (Tabas-Columbia), 3) regulation and function of lipid transfer proteins (Tall-Columbia), 4) macrophage lipid uptake, efflux and atherosclerosis (Smith-RU-subcontract Tall-Columbia). All of these projects are consonant with the theme of the PPG and will make extensive use of the transgenic animal core for the creation of transgenic animal core for the creation of transgenic and knockout mice and cryopreservation of important strains. Moreover, a new expression profiling core is proposed which will utilize new array technology to assess changes in gene expression; this approach will be combined with linkage analysis to aid in the discovery of new atherosclerosis susceptibility genes and will also be used to identify new target genes that are up-regulated by sterols, cAMP or apoptosis in macrophages. These studies are likely to contribute important new information relevant to human atherosclerosis that may lead to new diagnostic methods or therapies
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