This Program Project received a priority score of 155 on March 20, 2008. In this amended application we have corrected each and every one of the weaknesses identified by the Special Review Committee (SRC). These changes have included dropping specific aims or sub-aims in Projects 3-4-5-6, obtaining additional expertise (Project 6), adding experiments suggested by the reviewers (all Projects) and providing power calculations (Projects 3 and 5) as requested by the reviewers. We have also responded to the review by proposing a sophisticated integrated database system that will be maintained in Core D as recommended by the SRC. The intersection of inflammation and lipid metabolism in atherosclerosis is the theme of this Program Project. Project 1 will identify the pivotal regulators of a gene network that responds to oxidized phospholipids (Ox-PAPC/PEIPC) using cell biology and bioinformatics approaches. Project 2 will determine the mechanisms by which apolipoprotein mimetic peptides dramatically reduce inflammation and atherosclerosis. Project 3 will focus on Matrix Gla Protein (MGP) and the hepatic ABC transporter 6 (Abcc6) to determine the molecular mechanisms regulating vascular calcification and atherosclerosis. Project 4 will determine the molecular and cellular mechanisms by which ABC transporter G1 (ABCG1) regulates intracellular sterol movement and alters macrophage and lymphocyte function in atherosclerosis. Project 5 will use an integrative genetics approach to study the interactions of vascular cells, macrophages, and lipids as they relate to atherogenesis. Project 6 will determine the mechanisms by which interferon regulatory factor 3 (IRF3) signaling regulates the function of the liver X receptor (LXR) and cholesterol metabolism in atherosclerosis and the mechanisms by which the NR4A nuclear receptors mediate metabolic-immune crosstalk in atherosclerosis. These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis.
Work from this Program Project led major pharmaceutical firms to initiate testing of three of our discoveries from the current grant cycle as possible novel therapeutic approaches: apoA-l mimetic peptides;inhibitors of the 5-LO pathway, and selective agonists of LXRbeta. The studies proposed for the next grant cycle likely will elucidate molecular mechanisms that may provide the basis for other novel therapeutic approaches.
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