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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Mack, Julia J; Iruela-Arispe, M Luisa (2018) NOTCH regulation of the endothelial cell phenotype. Curr Opin Hematol 25:212-218
Beceiro, Susana; Pap, Attila; Czimmerer, Zsolt et al. (2018) LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. Mol Cell Biol :
Sallam, Tamer; Jones, Marius; Thomas, Brandon J et al. (2018) Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med 24:304-312
Skye, Sarah M; Zhu, Weifei; Romano, Kymberleigh A et al. (2018) Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res 123:1164-1176
Lin, Liang-Yu; Chun Chang, Sunny; O'Hearn, Jim et al. (2018) Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans. G3 (Bethesda) 8:3499-3506
Rahmani, Elior; Schweiger, Regev; Shenhav, Liat et al. (2018) BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference. Genome Biol 19:141
Chattopadhyay, Arnab; Yang, Xinying; Mukherjee, Pallavi et al. (2018) Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer. Sci Rep 8:9032
Hui, Simon T; Kurt, Zeyneb; Tuominen, Iina et al. (2018) The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68:2182-2196
Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A et al. (2018) An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures. Genetics 209:685-698
Seldin, Marcus M; Koplev, Simon; Rajbhandari, Prashant et al. (2018) A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism. Cell Metab 27:1138-1155.e6

Showing the most recent 10 out of 791 publications