Atherosclerosis is the leading cause of death in the United States and is now widely recognized as a chronic inflammatory disease occurring within the artery wall. The macrophage is the key innate immune cell type implicated in atherogenic inflammation, a pathophysiology largely driven by alterations in transcription. Work over the past two decades has identified pathways initiated through cell surface toll-like and cytokine receptors which culminate in the activation of NF-kB, AP1, and Stat proteins and subsequent transcriptional activation of pro-inflammatory genes encoding cytokines, chemokines, and matrix remodeling enzymes. The means and mechanisms by which pro-inflammatory genes are attenuated, however, remain poorly understood. Peroxisome proliferator activated receptors (PPARs) are lipid-sensing nuclear receptors and represent a nexus between nutrition, metabolism, and inflammation. Importantly, two PPAR isotypes are expressed in macrophages, PPARg and PPARd, and synthetic activators of each of these receptors are anti-inflammatory and anti-atherosclerotic in mouse models. Little is known about the molecular mechanisms underlying these therapeutic effects, but existing data suggest that interactions with the represser proteins NCoR and BCL6 may be central to their anti-inflammatory actions. A central hypothesis of this proposal is that inflammation can be modulated at the transcriptional level by PPARs and their repressors. We will elucidate roles for three components of the PPAR repressor complex, including BCL6, SMRT, and NCoR in macrophage- elicited inflammation, atherogenesis, and PPAR anti-inflammatory control. Experiments will take advantage of unique mouse knockout, knock-in, and knock-down models and utilize biochemical, molecular, and physiologic approaches.

Public Health Relevance

These studies will further our understanding of inflammation and atherosclerosis, focusing on the mechanisms by which PPARd exerts its anti-inflammatory effects. Insights from this work may identify targets for new types of anti-inflammatory drugs or next-generation PPAR compounds designed to improve the treatment of atherosclerosis and other inflammatory diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Carlson, Drew E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Salk Institute for Biological Studies
La Jolla
United States
Zip Code
Uhlenhaut, N Henriette; Barish, Grant D; Yu, Ruth T et al. (2013) Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell 49:158-71
Ding, Ning; Yu, Ruth T; Subramaniam, Nanthakumar et al. (2013) A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153:601-13
Barish, Grant D; Yu, Ruth T; Karunasiri, Malith S et al. (2012) The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis. Cell Metab 15:554-62
Yamamoto, Hiroyasu; Williams, Evan G; Mouchiroud, Laurent et al. (2011) NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147:827-39
Barish, Grant D; Yu, Ruth T; Karunasiri, Malith et al. (2010) Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes Dev 24:2760-5