In recent years, it has become accepted that immune cells play an active role in atherogenesis. Through various mouse studies, different subsets of lymphocytes have been shown to contribute to the atherosclerotic burden. However, mechanisms for how these cells contribute to atherogenesis or atheroprotection are not clearly understood. Moreover, an emerging concept is that lymphocytes and macrophages must communicate in the artery wall, but how this crosstalk influences atherogenesis is not clearly defined. In this PPG, we will study the immunobiology of atherosclerosis, with the goal of understanding how macrophages and lymphocytes communicate in the aortic wall to odulate atherogenesis. The PPG is comprised of three Projects and two Cores. In Project 1, Dr Hedrick will investigate how T regulatory lymphocyte function is changed during atherogenesis and subjects with Type 2 diabetes. In Project 2, Drs. Miller and Witztum will investigate how oxidized cholesteryl esters modulate TLR signaling in macrophages to influence metabolic endotoxemia and atherogenesis. Project 3 (McNamara) will study how B cells confer atheroprotection, and how the ranscriptional repressor Id3 influences B cell function in the aortic wall. The development of these projects involves extensive collaborations among all investigators. The Projects will be supported by two Cores, an Administrative Core and a Human Phenotyping and Immune Cell Core. This Human Core provides a translational aspect to our Program, providing blood samples, extensive subject phenotyping, and atherosclerosis assessment for subjects with and without Type 2 diabetes. As cardiovascular disease is a major risk factor for subjects with Type 2 diabetes, having access to such samples is a unique translational opportunity for our Program. Each project will utilize the Human Core to study immune cells from human subjects to establish functional links between candidate genes of interest and immune cell function in atherogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL055798-16A1
Application #
8339636
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Liu, Lijuan
Project Start
1997-09-08
Project End
2017-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$2,006,008
Indirect Cost
$342,741
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Tsimikas, Sotirios; Duff, Gordon W; Berger, Peter B et al. (2014) Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 63:1724-34
Willeit, Peter; Kiechl, Stefan; Kronenberg, Florian et al. (2014) Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 64:851-60
Ai, Ding; Jiang, Hongfeng; Westerterp, Marit et al. (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114:1576-84
Manichaikul, Ani; Rich, Stephen S; Perry, Heather et al. (2014) A functionally significant polymorphism in ID3 is associated with human coronary pathology. PLoS One 9:e90222
Lazic, Milos; Inzaugarat, Maria Eugenia; Povero, Davide et al. (2014) Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One 9:e107658
Cheng, Hsin-Yuan; Wu, Runpei; Hedrick, Catherine C (2014) Gammadelta (??) T lymphocytes do not impact the development of early atherosclerosis. Atherosclerosis 234:265-9
Morris-Rosenfeld, Samuel; Lipinski, Michael J; McNamara, Coleen A (2014) Understanding the role of B cells in atherosclerosis: potential clinical implications. Expert Rev Clin Immunol 10:77-89
Fang, Longhou; Liu, Chao; Miller, Yury I (2014) Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis. Transl Res 163:99-108
Ge, Shuwang; Hertel, Barbara; Koltsova, Ekaterina K et al. (2013) Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A. Circ Res 113:965-74
Cheng, Hsin-Yuan; Wu, Runpei; Gebre, Abraham K et al. (2013) Increased cholesterol content in gammadelta (ýýýý) T lymphocytes differentially regulates their activation. PLoS One 8:e63746

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