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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|Joo, Jong Wha J; Sul, Jae Hoon; Han, Buhm et al. (2014) Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies. Genome Biol 15:r61|
|Mangul, Serghei; Caciula, Adrian; Al Seesi, Sahar et al. (2014) Transcriptome assembly and quantification from Ion Torrent RNA-Seq data. BMC Genomics 15 Suppl 5:S7|
|Albright, Jody; Quizon, Pamela M; Lusis, Aldons J et al. (2014) Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery. BMC Med Genomics 7:51|
|Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong et al. (2014) Identifying causal variants at loci with multiple signals of association. Genetics 198:497-508|
|Lüscher, Thomas F; Landmesser, Ulf; von Eckardstein, Arnold et al. (2014) High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target. Circ Res 114:171-82|
|Jumabay, Medet; Abdmaulen, Raushan; Ly, Albert et al. (2014) Pluripotent stem cells derived from mouse and human white mature adipocytes. Stem Cells Transl Med 3:161-71|
|Ghazalpour, Anatole; Bennett, Brian J; Shih, Diana et al. (2014) Genetic regulation of mouse liver metabolite levels. Mol Syst Biol 10:730|
|Han, Buhm; Kang, Eun Yong; Raychaudhuri, Soumya et al. (2014) Fast pairwise IBD association testing in genome-wide association studies. Bioinformatics 30:206-13|
|Hasin-Brumshtein, Yehudit; Hormozdiari, Farhad; Martin, Lisa et al. (2014) Allele-specific expression and eQTL analysis in mouse adipose tissue. BMC Genomics 15:471|
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