Atherosclerosis is a chronic inflammatory disease of the arterial wall. THis has been established by studies of specific inflammatory gene deletions in hyperlipidemic mice that influence disease severity, the Toll-like receptors (TLR) of the innate immune system, which sense pathogens and mediate cell activation, can provide an important link between infection, inflammation and atherosclerosis. We discovered that TLR2-mediated inflammation influences disease progression in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic inflammatory TLR2-mediated responses to unknown endogenous agonists are mediated by non bone marrow-derived cells including endothelial cells, smooth muscle cells and advential fibroblasts. In contrast the proatherogenic inflammatory responses to the known exogenous, synthetic TLR2 agonist, Pam3, are mediated by bone marrow-derived cells including macrophages. In Project 4 of this program project grant we will confirm that TLR2-mediated cell activation by either endogenous or exogenous TLR2 agonists is predominately proatherogenic and analyze how TLR2-mediated inflammation influences atherosclerosis.
In Aim 1 we will study endogenous agonists of TLR2. We will characterize region-specific expression of TLR2 in vivo in non-bone marrow-derived cells and document the time course of the effect of TLR2 on macrophage infiltration into lesions. We will identify candidate endogenoous proatherogenic agonists and define the role of the TLR2 co-receptors, TLR1, TLR6 and CD36 in TLR2 signaling.
In Aim 2 we will study exogenous agonists of TLR2. We will determine if macrophages are sufficient for mediating proatherogenic inflammation induced by defined exogenous agonists. We will define the role of the TLR2 co-receptors with known exogenous agonists. These studies will enhance our understanding of inflammatory responses in atherosclerosis and potentially identify new TLR targets for therapeutic intervention to reduce disease risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088093-05
Application #
8375395
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$468,837
Indirect Cost
$338
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sherman, Mara H; Yu, Ruth T; Tseng, Tiffany W et al. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A 114:1129-1134
Fan, Weiwei; Evans, Ronald M (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab 25:242-247
Choi, Soo-Ho; Sviridov, Dmitri; Miller, Yury I (2017) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta 1862:393-397
He, Nanhai; Fan, Weiwei; Henriquez, Brian et al. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114:12542-12547
Shalapour, Shabnam; Lin, Xue-Jia; Bastian, Ingmar N et al. (2017) Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340-345
van Capelleveen, Julian C; Bernelot Moens, Sophie J; Yang, Xiaohong et al. (2017) Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 37:1206-1212
Fan, Weiwei; Waizenegger, Wanda; Lin, Chun Shi et al. (2017) PPAR? Promotes Running Endurance by Preserving Glucose. Cell Metab 25:1186-1193.e4
Doktorova, Marcela; Zwarts, Irene; Zutphen, Tim van et al. (2017) Intestinal PPAR? protects against diet-induced obesity, insulin resistance and dyslipidemia. Sci Rep 7:846
Wang, Jianrong; He, Nanhai; Zhang, Na et al. (2017) NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection. Nat Commun 8:959
Liu, Chao; Gaudet, Daniel; Miller, Yury I (2017) Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients. PLoS One 12:e0169939

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