Anti-atherogenic functions of HDL are likely linked to its ability to mediate several steps of the reverse cholesterol transport, including the rate-limiting cellular cholesterol efflux, and to its anti-oxidative and anti-inflammatory effects. Mounting evidence supports the concept that HDL may lose its functionality in some circumstances and disease states, and that HDL dysfunction contributes to the development and progression of atherosclerosis. The goal of our research is to define the mechanisms for HDL dysfunction in three common chronic diseases associated with elevated risk of atherosclerotic cardiovascular disease: Familial Hypercholesterolemia (FH), Rheumatoid Arthritis (RA), and Chronic Kidney Disease (CKD). The driving hypothesis of our proposal is that excessive oxidative burden will impair HDL's ability to regulate tissue levels of oxidative products, reduce its anti-inflammatory properties, and diminish its ability to promote cholesterol efflux from cells such as arterial macrophages. Core B will be an integral part of the PPG by providing both preparative and analytical services for isolation and analysis of lipoproteins, separation and preparation of lipoprotein components, and in vitro assays of HDL function using macrophages and other cell types.
Aim 1 is to provide isolation and analysis of lipoproteins, including HDL subfractions and apoproteins, including apoAl and apoAII, for functional studies and analyses of protein modifications.
Aim 2 is to provide assays for HDL functions, including the promotion of cholesterol efflux from macrophages and the control of inflammation and oxidation using established and validated cell-based and cell-free methods. Our methods to study cellular cholesterol losses takes into account both influx and efflux, and uses actual HDL as cholesterol acceptor. Core B provides a number of services to investigators that require unique instrumentation and methodologies and demand rigorous standardization procedures. It would be costly, inefficient, and cumbersome to establish these procedures in the laboratories of individual PPG investigators. The consolidation of these services into one laboratory provides investigators with efficient, high quality, low-cost analyses. Other objectives of Core B include: 1. To provide education and training to investigators, fellows, and research technicians on the science and methods of lipoprotein preparation and function, and on the best use of and logistical access to the services provided;2. To assist investigators in the development of methodologies a-la-carte, depending on experimental needs not currently foreseen.

Public Health Relevance

This PPG application is based on a reliable and consistent production of reagents such as lipoproteins and monocytes, the uniform conduct of very sensitive functional assays such as cholesterol extraction from loaded cells, and a standardized analysis and interpretation of results. Core B will assure consistency, reliability, and standardization for all procedures and tests. This will fuel cross-pollination and increase cohesiveness and comparability of data among projects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL116263-01A1
Application #
8693116
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
$254,618
Indirect Cost
$91,997
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ormseth, Michelle J; Stein, C Michael (2016) High-density lipoprotein function in rheumatoid arthritis. Curr Opin Lipidol 27:67-75
Ormseth, Michelle J; Yancey, Patricia G; Solus, Joseph F et al. (2016) Effect of Drug Therapy on Net Cholesterol Efflux Capacity of High-Density Lipoprotein-Enriched Serum in Rheumatoid Arthritis. Arthritis Rheumatol 68:2099-105
Babaev, Vladimir R; Yeung, Michele; Erbay, Ebru et al. (2016) Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice. Arterioscler Thromb Vasc Biol 36:1122-31
Michell, Danielle L; Vickers, Kasey C (2016) HDL and microRNA therapeutics in cardiovascular disease. Pharmacol Ther 168:43-52
Yang, Haichun; Fogo, Agnes B; Kon, Valentina (2016) Kidneys: key modulators of high-density lipoprotein levels and function. Curr Opin Nephrol Hypertens 25:174-9
Kon, Valentina; Linton, MacRae F (2016) HDL: Beyond Atheroprotection. J Am Soc Nephrol 27:341-4
Babaev, Vladimir R; Ding, Lei; Zhang, Youmin et al. (2016) Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis. Arterioscler Thromb Vasc Biol 36:598-607
Beavers, Kelsey R; Werfel, Thomas A; Shen, Tianwei et al. (2016) Porous Silicon and Polymer Nanocomposites for Delivery of Peptide Nucleic Acids as Anti-MicroRNA Therapies. Adv Mater 28:7984-7992
Cheung, Kei-Hoi; Keerthikumar, Shivakumar; Roncaglia, Paola et al. (2016) Extending gene ontology in the context of extracellular RNA and vesicle communication. J Biomed Semantics 7:19
Michell, Danielle L; Vickers, Kasey C (2016) Lipoprotein carriers of microRNAs. Biochim Biophys Acta 1861:2069-2074

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