A long-term goal of our laboratory is to understand the role that lipid-activated transcription factors play in the coordination of metabolic and inflammatory gene expression in human disease. Work accomplished in the current grant period delineated new functions for LXR and NR4A nuclear receptors in the control of cholesterol and glucose metabolism and also revealed unexpected roles for these factors in immune responses. In the next funding period we propose to extend prior work to address the function of LXR in metabolic-immune crosstalk on three levels: innate immune responses, acquired immune functions, and crosstalk between the innate and acquired immune systems. We further propose to build upon our discovery of the importance of NR4A nuclear receptors in the transcriptional control of both inflammation and metabolism. Collectively, these studies are expected to advance our understanding of the molecular pathways that integrate metabolic and inflammatory processes in physiology and disease.
Our first aim i s to test the hypothesis that metabolic activation of IRF3 signaling regulates LXR function and cholesterol metabolism. We will explore the impact of lipid mediators on IRF3 signaling and test the influence of IRF3- LXR crosstalk on the development of atherosclerosis.
Our second aim i s to test the hypothesis that lipiddependent LXR signaling is a physiologic modulator of lymphocyte function. We will determine mechanisms whereby cholesterol metabolism and LXR signaling regulate adaptive immune responses and the development of lymphocyte-dependent inflammatory diseases. We will also define the mechanistic basis for the immunomodulatory effects of synthetic LXR agonists.
Our third aim i s to define the impact of macrophage NR4A receptors on inflammation and the development of atherosclerosis using gain- and lossof- fucntion mouse models. We will test the involvement of NR4A receptors in crosstalk between inflammatory and metabolic signaling and determine the mechanisms underlying such crosstalk. Completion of these aims is expected to bring new insight into fundamental mechanisms underlying metabolism and inflammation and may suggest new opportunities for therapeutic intervention in cardiovascular disease.

Public Health Relevance

Crosstalk between metabolic and inflammatory signaling pathways plays an important role in metabolic diseases including atherosclerosis. We have uncovered new mechanisms involved linking metabolism and inflammation that may contribute to atherosclerosis. Further dissection of these pathways will provide insight into the pathogenesis of cardiovascular disease and may suggest new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030568-30
Application #
8446360
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
30
Fiscal Year
2013
Total Cost
$308,268
Indirect Cost
$108,095
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hormozdiari, Farhad; van de Bunt, Martijn; Segrè, Ayellet V et al. (2016) Colocalization of GWAS and eQTL Signals Detects Target Genes. Am J Hum Genet 99:1245-1260
Seldin, Marcus M; Meng, Yonghong; Qi, Hongxiu et al. (2016) Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-κB. J Am Heart Assoc 5:
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Shufelt, Chrisandra; Elboudwarej, Omeed; Johnson, B Delia et al. (2016) Carotid artery distensibility and hormone therapy and menopause: the Los Angeles Atherosclerosis Study. Menopause 23:150-7
Meriwether, David; Sulaiman, Dawoud; Wagner, Alan et al. (2016) Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux. J Lipid Res 57:1175-93
Duong, Dat; Zou, Jennifer; Hormozdiari, Farhad et al. (2016) Using genomic annotations increases statistical power to detect eGenes. Bioinformatics 32:i156-i163
Tarling, Elizabeth J; Edwards, Peter A (2016) Intracellular Localization of Endogenous Mouse ABCG1 Is Mimicked by Both ABCG1-L550 and ABCG1-P550-Brief Report. Arterioscler Thromb Vasc Biol 36:1323-7
Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg et al. (2016) Tg6F ameliorates the increase in oxidized phospholipids in the jejunum of mice fed unsaturated LysoPC or WD. J Lipid Res 57:832-47
Hormozdiari, Farhad; Kang, Eun Yong; Bilow, Michael et al. (2016) Imputing Phenotypes for Genome-wide Association Studies. Am J Hum Genet 99:89-103
Lusis, Aldons J; Seldin, Marcus M; Allayee, Hooman et al. (2016) The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits. J Lipid Res 57:925-42

Showing the most recent 10 out of 743 publications