Project Summary / Abstract Heart disease accounts for 1 in 7 of all deaths in the USA, the majority of which are caused by atherosclerotic plaques. Atherosclerosis and its complications are the leading cause of disability and deaths worldwide. In addition, they also significantly contribute to the health care financial burden. Therefore, there is a clear need for the development of novel therapies aimed at new signaling pathways and gene targets. Treatment strategies targeting broad inflammatory and metabolic gene programs are desirable to achieve complete cessation and reversal of plaque development. There is an increasing appreciation that transcriptionally dynamic macrophages are a key player in the pathogenesis of atherosclerosis. We have established that CITED2 represents a molecular “switch,” that promotes anti-atherogenic macrophage activation while repressing harmful pro-atherogenic phenotypes. Our preliminary studies revealed that, (a) CITED2 expression is attenuated in human and murine atherosclerotic plaque macrophages; (b) Anti-atherogenic stimuli enhance and pro-atherogenic agents attenuate CITED2 expression in human, and murine macrophages; (c) Deficiency of Cited2 enhance macrophage lipid accumulation and foam cell formation; (d) Reduction in Cited2 expression results in heightened basal levels of lipid influx gene while significantly diminished lipid metabolism and efflux gene expression; (e) Myeloid-specific deficiency of Cited2 significantly elevated high-fat diet induced atherosclerotic lesion formation in vivo. (f) Cited2 executes atheroprotective functions by cooperating with PPARγ while antagonizing IRF1 activation in macrophages. Based on these observations, we hypothesize that CITED2 is a critical negative regulator of macrophage pro-inflammatory activation, foam cell formation and atherogenesis. We propose following aims to determine the precise role macrophage CITED2 in the pathogenesis of atherosclerosis. In Aim 1: To dissect the precise molecular mechanism by which CITED2 regulates macrophage inflammatory and lipid homeostasis gene expression. In Aim 2: To investigate the role of CITED2 in macrophage lipid homeostasis and foam cell formation. In Aim 3: To examine the impact of myeloid-CITED2 deficiency on the pathogenesis of atherosclerosis. At the conclusion of these studies, we will have expanded our fundamental insights into the molecular role of CITED2 in atherogenesis. Thus, the outcome of our studies may provide novel opportunities to design therapeutic intervention in the treatment of human lipid metabolic disorders.