Our studies have demonstrated that phospholipid oxidation products (Ox-PAPC) which accumulate in atherosclerotic lesions are important regulators of endothelial cell function, affecting mRNA levels of over 1000 genes involving inflammation, sterol regulation, coagulation, oxidative stress, cell cycle, angiogenesis, redox regulation and the unfolded protein response. The inflammatory response to Ox-PAPC and to its component lipid PEIPC was shown to differ significantly from those of IPS and TNF, leading to a chronic upregulation of monocyte-endothelial interactions. A major goal of the proposed studies is to identify the pivotal regulators of the Ox-PAPC/PEIPC network using cell biology and bioinformatics approaches.
In Aim 1 we will use a cell biology approach to test three aspects of the basic signaling mechanism activated by Ox- PAPC and PEIPC. We will: define additional components of the Ox-PAPC receptor complex;determine how Ox-PAPC and PEIPC alter the cellular redox balance to contol gene expression;and determine whether covalent binding of PEIPC to proteins is important in activation.
In Aim 2, we will use an integrative genetics approach to define the overall network at the transcript level, leveraging the concept that common genetic variations in the population can be used to organize expression array data into biologically relevant modules. We will map the genes contributing to common variation in the network using genome-wide association and integrate the data with orthogonal proteomic and functional datasets.
Aims 1 and 2 will also include validation of important regulators by use of siRNA and in some cases overexpression.
In Aim 3 we will determine whether endothelial expression of three important network regulators (SREBP, STAT3 and HO-1) plays an important role in atherosclerosis in mice. For these studies, we will employ LDL receptor null mice with endothelial specific knockout of these proteins. In addition, inflammatory areas of human lesions will be examined for expression and activation of these molecules and others we find to regulate the network. Together, these studies will identify potential endothelial targets for the control of atherosclerosis.

Public Health Relevance

Oxidized phospholipids accumulate in atherosclerotic lesions and likely contribute to initiating and sustaining the disease. These studies will determine the mechanism of endothelial cell activation by these lipids to initiate inflammation and thrombosis. In addition they will identify genetic polymorphisms that contribute to endothelial activation for use as prognostic and therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030568-30
Application #
8446355
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
30
Fiscal Year
2013
Total Cost
$410,425
Indirect Cost
$143,915
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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