Project 2 will focus on apolipoprotein mimetic peptides. Because these compounds appear to have generalized anti-inflammatory properties, this information is likely to be highly informative of rate-limiting steps in inflammation, as well as in atherogenesis.
Aim 1 is to determine the mechanism(s) by which apoA-l mimetic peptides are anti-inflammatory at plasma concentrations that are orders of magnitude less than that of apoA-l. In patients with CHD and pro-inflammatory HDL, a single oral dose of D-4F produced plasma levels of ~4 nanomolar and significantly improved the anti-inflammatory properties of HDL. How could a concentration of ~4 nanomolar of an apoA-l mimetic peptide be effective when the concentration of apoA-l in the patient plasma was -35 micromolar? We hypothesize that the anti-inflammatory properties of apoA-l mimetic peptides derives from their ability to bind pro-inflammatory oxidized lipids with a KD many orders of magnitude less than human apoA-l. We hypothesize that the remarkable anti-inflammatory properties of apoA-l mimetic peptides also relate to their ability to inhibit pro-inflammatory cytokine production while not inhibiting the induction of anti-oxidant enzymes such as heme oxygenase-1 (HO-1).
Aim 2 is to investigate the mechanism(s) by which apolipoprotein mimetic peptides reduce the content of heme-binding and hemecontaining proteins in HDL and reduce vascular inflammation. Administration of an apoA-l mimetic peptide dramatically reduced these HDL-associated proteins. We hypothesize that the binding of these proteins to HDL causes iron to enter macrophages via pathways that stimulate the production of pro-inflammatory cytokines without stimulating anti-oxidant enzymes such as HO-1. We hypothesize that apoA-l mimetic peptides reduce the binding molecules in HDL for iron containing proteins, thus shifting these iron containing proteins away from HDL and allowing them to enter macrophages by pathways that do not stimulate proinflammatory cytokines but which do induce HO-1.
Aim 3 is to determine.the mechanism(s) by which niclosamide enables apolipoprotein mimetic peptides synthesized from all L-amino acids to be bioactive when administered orally.
Aim 4 is to determine the mechanism(s) by which apolipoprotein mimetic peptides promote apoA-l synthesis in the intestine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030568-29
Application #
8378580
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
29
Fiscal Year
2012
Total Cost
$400,224
Indirect Cost
$140,338
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hormozdiari, Farhad; van de Bunt, Martijn; Segrè, Ayellet V et al. (2016) Colocalization of GWAS and eQTL Signals Detects Target Genes. Am J Hum Genet 99:1245-1260
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Duong, Dat; Zou, Jennifer; Hormozdiari, Farhad et al. (2016) Using genomic annotations increases statistical power to detect eGenes. Bioinformatics 32:i156-i163
Tarling, Elizabeth J; Edwards, Peter A (2016) Intracellular Localization of Endogenous Mouse ABCG1 Is Mimicked by Both ABCG1-L550 and ABCG1-P550-Brief Report. Arterioscler Thromb Vasc Biol 36:1323-7
Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg et al. (2016) Tg6F ameliorates the increase in oxidized phospholipids in the jejunum of mice fed unsaturated LysoPC or WD. J Lipid Res 57:832-47
Hormozdiari, Farhad; Kang, Eun Yong; Bilow, Michael et al. (2016) Imputing Phenotypes for Genome-wide Association Studies. Am J Hum Genet 99:89-103
Lusis, Aldons J; Seldin, Marcus M; Allayee, Hooman et al. (2016) The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits. J Lipid Res 57:925-42

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