Atherosclerosis is now widely recognized as a chronic inflammatory disease involving a complex interplay between resident vascular endothelial and smooth muscle cells and infiltrating immune cells, particularly macrophages. An underlying hypothesis of this work is that inflammation can be modulated at the transcriptional level by nuclear receptors and their co-repressors. Previous studies in our laboratory identified PPARd as an """"""""inflammatory switch"""""""" within the macrophage, in which ligands act to control the concentrations of free and nuclear receptor-bound fractions of the co-repressors BCL-6 and SMRT. Biochemical, molecular, genetic, and physiologic approaches will be used to uncover the roles for these factors in inflammation and atherosclerosis. Finally, we will examine functions for PPARs throughout the artery wall and atherosclerotic lesion by utilizing conditional knockout models of PPARg and PPARd in the vascular endothelium. Studies will include both molecular and cell biology experiments and in vivo experiments, taking advantage of unique nuclear receptor knockout and conditional knockout-derived cells and mouse models using newly developed orally active PPARd-specific drugs along with the available class of PPARg therapeutics.
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