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
Mack, Julia J; Iruela-Arispe, M Luisa (2018) NOTCH regulation of the endothelial cell phenotype. Curr Opin Hematol 25:212-218
Beceiro, Susana; Pap, Attila; Czimmerer, Zsolt et al. (2018) LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis. Mol Cell Biol :
Sallam, Tamer; Jones, Marius; Thomas, Brandon J et al. (2018) Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med 24:304-312
Skye, Sarah M; Zhu, Weifei; Romano, Kymberleigh A et al. (2018) Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res 123:1164-1176
Lin, Liang-Yu; Chun Chang, Sunny; O'Hearn, Jim et al. (2018) Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans. G3 (Bethesda) 8:3499-3506
Rahmani, Elior; Schweiger, Regev; Shenhav, Liat et al. (2018) BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference. Genome Biol 19:141
Chattopadhyay, Arnab; Yang, Xinying; Mukherjee, Pallavi et al. (2018) Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer. Sci Rep 8:9032
Hui, Simon T; Kurt, Zeyneb; Tuominen, Iina et al. (2018) The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68:2182-2196
Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A et al. (2018) An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures. Genetics 209:685-698
Seldin, Marcus M; Koplev, Simon; Rajbhandari, Prashant et al. (2018) A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism. Cell Metab 27:1138-1155.e6

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