Paraoxonases (PON), a family of orphan enzymes with multiple enzyme activities assigned to them, comprise of three proteins PON1, PON2, and PON3. The aryl esterase, organophosphatase, and lipo-lactonase activities of PON enzymes underscore their importance in inflammation, toxicology, and infection, respectively. Epidemiological studies identified PON proteins in the etiology of a number of inflammatory diseases including cardiovascular diseases. Sequence analysis of PON genes suggest that the PON family evolved by gene duplication with PON2 being the first and PON1 the most recent member. Interestingly, PON2 and PON3 are predominantly localized to intracellular compartments while PON1 is found exclusively extracellular and associated solely with HDL particles. Our laboratory has cloned and characterized both PON2 and PON3 genes, and also developed mouse models for studying the role of PON2 and PON3 in atherosclerosis. Recent studies suggest that PON2 and PON3 are associated with mitochondria and mitochondrial associated membranes and play important roles in the modulation of mitochondrial oxidative stress. PON2 protects against the development of atherosclerosis and insulin resistance. Moreover, macrophage PON2 plays a critical role in the mechanisms that mediate both the development of atherosclerosis and insulin resistance. PON3 protects against the development of atherosclerosis and obesity. Despite the role of PON2 and PON3 in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON2 and PON3 function as anti-atherogenic and anti-inflammatory proteins are largely unknown. In this application, we propose to i. delineate the physiological substrates for PON2 and PON3 proteins, ii. determine the molecular mechanisms by which PON2 and PON3 function, and iii. to examine the role of PON2 and PON3 proteins in vascular inflammatory diseases including diabetes, obesity, and ischemic heart disease. These studies will help identify novel molecular targets for the treatment of inflammatory diseases

Public Health Relevance

PON2 and PON3 proteins play important roles in a number of vascular and inflammatory diseases. Based on recent discoveries in our laboratory, we propose experimental strategies that will allow us to, for the first time, identify the physiological substrates and determine the mechanisms by which PON2 and PON3 proteins function. Successful completion of these studies will identify novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL071776-09
Application #
8577944
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2003-01-01
Project End
2018-05-31
Budget Start
2013-07-19
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$366,520
Indirect Cost
$128,520
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
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