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 #
5P01HL030568-29
Application #
8378578
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
$431,117
Indirect Cost
$151,171
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hormozdiari, Farhad; Zhu, Anthony; Kichaev, Gleb et al. (2017) Widespread Allelic Heterogeneity in Complex Traits. Am J Hum Genet 100:789-802
Bilow, Michael; Crespo, Fernando; Pan, Zhicheng et al. (2017) Simultaneous Modeling of Disease Status and Clinical Phenotypes To Increase Power in Genome-Wide Association Studies. Genetics 205:1041-1047
Mack, Julia J; Mosqueiro, Thiago S; Archer, Brian J et al. (2017) NOTCH1 is a mechanosensor in adult arteries. Nat Commun 8:1620
Org, Elin; Blum, Yuna; Kasela, Silva et al. (2017) Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort. Genome Biol 18:70
Pillai, Indulekha C L; Li, Shen; Romay, Milagros et al. (2017) Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell Stem Cell 20:218-232.e5
von Scheidt, Moritz; Zhao, Yuqi; Kurt, Zeyneb et al. (2017) Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis. Cell Metab 25:248-261
Yao, Jiayi; Guihard, Pierre J; Wu, Xiuju et al. (2017) Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. J Cell Biol 216:3369-3385
Mukherjee, Pallavi; Hough, Greg; Chattopadhyay, Arnab et al. (2017) Transgenic tomatoes expressing the 6F peptide and ezetimibe prevent diet-induced increases of IFN-? and cholesterol 25-hydroxylase in jejunum. J Lipid Res 58:1636-1647
Schugar, Rebecca C; Shih, Diana M; Warrier, Manya et al. (2017) The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. Cell Rep 19:2451-2461
Rong, Xin; Wang, Bo; Palladino, Elisa Nd et al. (2017) ER phospholipid composition modulates lipogenesis during feeding and in obesity. J Clin Invest 127:3640-3651

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