ABCG1 is a cholesterol transporter involved in the efflux of cholesterol to HDL in reverse cholesterol transport. In the prior funding period, we discovered that mouse models of Type 2 diabetes as well as human subjects with Type 2 diabetes have decreased ABCG1 expression and function. We also uncovered an important intracellular role of ABCG1 and sterols in regulation of T cell proliferation and activation. We will extend these fundings in this new funding period to study how T cell homeostasis and activation are changed during atherosclerosis progression as well as in Type 2 diabetes. We will use a combination of studies in mice and in humans to address these questions. In collaboration with Project 3, (McNamara), we will study how Id3 regulates Tregulatory (Treg) phenotypes;in collaboration with Project 2 (Miller), we will examine how oxidized lipids influence Treg and monocyte phenotypes in atherogenesis. We will also obtain blood samples from the Human Phenotyping and Immune Cell Core to measure the cholesterol content and inflammatory phenotype of T cells isolated from subjects with atherosclerosis and/or with Type 2 diabetes. We will correlate these T cell measurements with clinically measured parameters for atherosclerosis and type 2 diabetes, such as carotid artery intima-media thickness (CIMT), hemoglobin Ale (HbAlc), and plasma lipoprotein levels. This project is directly related to the PPG theme of uncovering mechanisms contributing to the immunobiology of atherosclerosis.

Public Health Relevance

Despite significant advances in identifying immune cells that participate in atherogenesis, little is known about their mechanisms of action in the artery wall. We propose a novel mechanism by which sterols and the setting of Type 2 diabetes regulate T regulatory cell proliferation and phenotype to influence early events in atherogenesis in the vessel wall.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL055798-18
Application #
8707523
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Prasad, Anand; Clopton, Paul; Ayers, Colby et al. (2017) Relationship of Autoantibodies to MDA-LDL and ApoB-Immune Complexes to Sex, Ethnicity, Subclinical Atherosclerosis, and Cardiovascular Events. Arterioscler Thromb Vasc Biol 37:1213-1221
Miller, Yury I; Shyy, John Y-J (2017) Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation. Trends Endocrinol Metab 28:143-152
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
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Ley, Klaus; Gerdes, Norbert; Winkels, Holger (2017) ATVB Distinguished Scientist Award: How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis. Arterioscler Thromb Vasc Biol 37:764-777
Yeang, Calvin; Gordts, Philip L S M; Tsimikas, Sotirios (2017) Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. Circ Res 120:1050-1052
Pechlaner, Raimund; Tsimikas, Sotirios; Yin, Xiaoke et al. (2017) Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol 69:789-800
Lee, Sang-Rok; Prasad, Anand; Choi, Yun-Seok et al. (2017) LPA Gene, Ethnicity, and Cardiovascular Events. Circulation 135:251-263
Nowyhed, Heba N; Chandra, Shilpi; Kiosses, William et al. (2017) ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content. Sci Rep 7:40273
Choi, Soo-Ho; Sviridov, Dmitri; Miller, Yury I (2017) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta 1862:393-397

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