The overall aim of the program project is to assess the contribution of HDL dysfunction to three conditions that increase risk for atherosclerosis: familial hypercholesterolemia, chronic kidney disease, and rheumatoid arthritis. One mechanism of HDL dysfunction that these conditions appear to share is the presence of oxidative stress, which has led to one of the main hypotheses in this program: that peroxidation of HDL in these conditions causes it to become dysfuncfional. Core C will assist in this endeavor by measuring levels of various products of lipid peroxidation in HDL and by providing reagents to directly test the contribution of these oxidized products to HDL dysfunction. Core C has three aims: 1) To synthesize two classes of compounds that will be utilized in all 3 Projects. The first will be synthetic isoprostane products including F2-isoprostane containing phospholipids, gamma-ketoaldehydes (isolevuglandin/isoketal), and inactive analogs which will be used primarily by project 3. The second class of compounds will be aldehyde scavengers and their inactive analogs which will be used by all 3 projects. 2) To quantify lipid peroxidation products in clinical and animal samples using mass spectrometric techniques. These products will include F2-isoprostane, isolevuglandin-lysine-adducts, isolevuglandin-PE adducts, and MDA-lysine crosslinks. This service will be utilized by all 3 Projects. 3) To quantify plasma levels of aldehydes scavengers and their inactive analogs in mice administered these compounds which include salicylamine, 4-salicylamine, pentylpyridoxamine, and pentylpyridoxine. This service will be utilized by all 3 projects.

Public Health Relevance

Cardiovascular disease is the major cause of death in the Western world. Analyzing for presence of oxidation products in HDL and studying how these correlate with atherosclerosis will help us understand the role of these products in disease. By synthesizing compounds that block specific oxidation products, we will be able to determine if these can function as treatment for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL116263-01A1
Application #
8693117
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$240,339
Indirect Cost
$87,094
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Allen, Ryan M; Vickers, Kasey C (2014) Coenzyme Q10 increases cholesterol efflux and inhibits atherosclerosis through microRNAs. Arterioscler Thromb Vasc Biol 34:1795-7