EXCEED THE SPACE PROVIDED. A number of pathophysiological observations in humans and animal models led to the hypothesis that atherosclerosis, a disease of the large arteries that is the primary cause of coronary heart disease (CHD) and stroke, is a multifactorial chronic inflammatory disease in which low plasma levels of HDL and high plasma levels of LDL, are a strong predictor of the condition. LDL oxidation is considered to be an essential process in the development of atherosclerotic lesions. The pro-inflammatory constituents of oxidized LDL are various oxidized phospholipids resulting from the scission and rearrangement of oxidized, unsaturated fatty acids. HDL and HDL-associated enzymes possess anti-atherogenic properties that are due, in part, to their inactivation of oxidized LDL. Athough genetic and biochemical studies demonstrated anti-atherogenic role for paraoxanase-1 (PON1), a HDL associated protein, to date, the physiological functions of PON family of proteins; PON1, PON2 and PON3, remain unknown. Based on our preliminary findings, we hypothesize that PON2 and PON3 proteins inhibit the accumulation of oxidized phospholipids in LDL, protect artery wall cells against oxidative stress from reactive oxygen species (ROS) and oxidized phospholipids, and prevent the development of atherosclerotic lesions. In this grant, we propose to i) characterize the biochemical and enzymatic properties of PON2 and PON3 proteins, ii) determine cellular localization, products of enzyme activity and the expression levels of PON2 and PON3 proteins in HDL and hyperchloesterolemic animal models, iii) develop transgenic mice and knockout mice to determine the physiological function of PON2 and PON3 proteins as well as the role of PON2 and PON3 in atherosclerosis, and iv) identify and characterize proteins that interact with PON2 and PON3 to delineate the biological substrates of PON2 and PON3 proteins. Understanding the biology and function of the PON proteins will pave way for the discovery of novel therapeutic agents in the fight against atherosclerosis and other inflammatory diseases. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071776-03
Application #
6836025
Study Section
Pathology A Study Section (PTHA)
Program Officer
Goldman, Stephen
Project Start
2003-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$343,125
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Devarajan, Asokan; Su, Feng; Grijalva, Victor et al. (2018) Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer. Cell Death Dis 9:392
Singh, Rajan; Pervin, Shehla; Lee, Se-Jin et al. (2018) Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases. Diabetes Metab Syndr Obes 11:65-84
Charles-Schoeman, C; Gugiu, G B; Ge, H et al. (2018) Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis. Atherosclerosis 275:107-114
Li, Wei; Kennedy, David; Shao, Zhili et al. (2018) Paraoxonase 2 prevents the development of heart failure. Free Radic Biol Med 121:117-126
Meriwether, David; Sulaiman, Dawoud; Wagner, Alan et al. (2016) Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux. J Lipid Res 57:1175-93
Mehta, Niyati U; Grijalva, Victor; Hama, Susan et al. (2016) Apolipoprotein E-/- Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function. Arterioscler Thromb Vasc Biol 36:1152-63
Mehta, Niyati U; Reddy, Srinivasa T (2015) Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases. Curr Opin Lipidol 26:384-7
Shih, Diana M; Yu, Janet M; Vergnes, Laurent et al. (2015) PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis. FASEB J 29:1185-97
Braga, Melissa; Reddy, Srinivasa T; Vergnes, Laurent et al. (2014) Follistatin promotes adipocyte differentiation, browning, and energy metabolism. J Lipid Res 55:375-84
Devarajan, Asokan; Shih, Diana; Reddy, Srinivasa T (2014) Inflammation, infection, cancer and all that…the role of paraoxonases. Adv Exp Med Biol 824:33-41

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