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.
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.
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|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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