Atherosclerosis is now widely recognized as a chronic inflammatory disease involving a complex interplaybetween resident vascular endothelial and smooth muscle cells and infiltrating immune cells, particularlymacrophages. An underlying hypothesis of this work is that inflammation can be modulated at thetranscriptional level by nuclear receptors and their co-repressors. Previous studies in our laboratoryidentified PPARd as an 'inflammatory switch' within the macrophage, in which ligands act to control theconcentrations 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 thesefactors in inflammation and atherosclerosis. Finally, we will examine functions for PPARs throughout theartery wall and atherosclerotic lesion by utilizing conditional knockout models of PPARg and PPARd in thevascular endothelium. Studies will include both molecular and cell biology experiments and in vivoexperiments, taking advantage of unique nuclear receptor knockout and conditional knockout-derived cellsand mouse models using newly developed orally active PPARd-specific drugs along with the available classof PPARg therapeutics
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