Abstract

The overall goal of this program project is to test the contribution of changes in high density lipoprotein (HDL) function in human disease, specifically atherosclerosis. One of the major hypotheses tested is that the lipid peroxidation that occurs during various condition that increase the risk for atherosclerosis (e.g. familial hypercholesterolemia and chronic kidney disease) causes HDL to become modified by reactive lipid dicarbonyls and that these modifications markedly alter HDL function. This core will provide synthetic versions of these reactive dicarbonyls to project investigators so that they can test the effects of HDL modification. This core will also provide synthetic compounds that act as dicarbonyl scavengers and that can be used in both cultured cells, in animals, and in humans to block the reaction of dicarbonys with proteins and phosphatidylethanolamine. These scavengers are useful both to test the contribution of these dicarbonyls and as potential medicinal agents. Finally, this core will measure dicarbonyl adducts on proteins and phosphatidylethanolamine.
Aim 1 : Synthesize IsoLG and other dicarbonyls for testing in cultured cell and animal models.
Aim 2 : Synthesize dicarbonyl scavengers for testing in cultured cell and animal models.
Aim 3 : Measure the amounts of dicarbonyl modified proteins and phosphatidylethanolamines that are formed in tissue samples and fluids in animal models and humans with disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL116263-06A1
Application #
10089338
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
2014-06-01
Project End
2025-12-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
6
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232

  Publications

Allen, Ryan M; Zhao, Shilin; Ramirez Solano, Marisol A et al. (2018) Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins. J Extracell Vesicles 7:1506198
Mueller, Paul A; Zhu, Lin; Tavori, Hagai et al. (2018) Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages. Circulation 138:1850-1863
Li, Kang; Rodosthenous, Rodosthenis S; Kashanchi, Fatah et al. (2018) Advances, challenges, and opportunities in extracellular RNA biology: insights from the NIH exRNA Strategic Workshop. JCI Insight 3:
Babaev, Vladimir R; Ding, Lei; Zhang, Youmin et al. (2018) Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice. Arterioscler Thromb Vasc Biol :ATVBAHA118312206
Kaseda, R; Tsuchida, Y; Gamboa, J L et al. (2018) Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis. Nutr Metab Cardiovasc Dis 28:582-591
Kaseda, Ryohei; Tsuchida, Yohei; Yang, Hai-Chun et al. (2018) Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. BMC Nephrol 19:17
Babaev, Vladimir R; Huang, Jiansheng; Ding, Lei et al. (2018) Loss of Rictor in Monocyte/Macrophages Suppresses Their Proliferation and Viability Reducing Atherosclerosis in LDLR Null Mice. Front Immunol 9:215
Byram, Kevin W; Oeser, Annette M; Linton, MacRae F et al. (2018) Exercise is Associated With Increased Small HDL Particle Concentration and Decreased Vascular Stiffness in Rheumatoid Arthritis. J Clin Rheumatol 24:417-421
Sedgeman, Leslie R; Beysen, Carine; Allen, Ryan M et al. (2018) Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes. Am J Physiol Gastrointest Liver Physiol :
May-Zhang, Linda S; Yermalitsky, Valery; Huang, Jiansheng et al. (2018) Modification by isolevuglandins, highly reactive ?-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function. J Biol Chem 293:9176-9187

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