PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in chronic kidney disease (CKD), reducing the life expectancy of CKD and dialysis patients to roughly half to one-third that of the general population. However, the pathogenesis of accelerated CVD in CKD is not yet clearly understood, and no specific therapeutic strategies are currently available to attenuate this phenomenon. Our long-term goal is to understand the immune-metabolic mechanisms underlying accelerated atherosclerosis in order to develop diagnostic and therapeutic solutions to improve the lifespan of patients with CKD. Our overall objective is to define the role of tryptophan catabolism via the kynurenine pathway (KP) in the pathophysiology of CKD atherosclerosis. Our central hypothesis is that the tryptophan catabolite kynurenic acid (KA) causes CKD atherosclerosis, whereas 3-hydroxy anthranilic acid (3-HAA) ameliorates this problem. Our rationale is that if KP metabolites play a causal role in CKD atherosclerosis, then we can develop new therapeutic strategies and biomarkers to attenuate the CVD burden in the CKD population. We will test our central hypothesis by pursuing the following specific aims: 1) demonstrating the role of circulating and macrophage-specific KA, and 2) delineating the anti-inflammatory role of circulating and macrophage 3-HAA in the pathogenesis of CKD atherosclerosis. Under Aim 1, we will delineate the effect of circulating KA, define the role of macrophage KA deficiency using in bio-banked human aortic specimens and CKD atherosclerosis models, and identify KA-induced macrophage molecular mechanisms like activation of aryl hydrocarbon and cell-membrane G protein-coupled receptor 35 pathways in the pathogenesis of CKD atherosclerosis. Regarding Aim 2, we plan to delineate the effect of circulating 3-HAA, define the role of macrophage 3-HAA using bio-banked aortic samples and CKD atherosclerosis models, and identify the 3-HAA induced macrophage mechanisms like inflammasome activation in the pathogenesis of CKD atherosclerosis. The proposed research is innovative in that it links macrophage inflammation and metabolism in CKD and delineates the contribution of lesional macrophage tryptophan metabolism vs. that of circulating KP metabolites in CKD atherosclerosis via mass spectrometric metabolic profiling and myeloid-specific KP deficiency in CKD atherosclerosis models. The proposed research is significant because it will provide strong evidence of the mechanistic role of tryptophan metabolism in the pathogenesis of CKD atherosclerosis, potentially leading to the discovery of validated biomarkers and clinical studies to prevent CV events in CKD atherosclerosis.