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.
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.
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