Tryptophan immune metabolism and vascular inflammation in CKD associated atherosclerosis

项目摘要/摘要 心血管疾病(CVD)是慢性肾脏疾病(CKD)发病率和死亡率的主要原因， 将慢性肾脏病和透析患者的预期寿命降低到普通患者的大约一半到三分之一 人口。然而，CKD中加速CVD的发病机制尚不清楚，也没有。 目前有特定的治疗策略可用于减轻这一现象。我们的长期目标是 了解加速动脉粥样硬化的免疫代谢机制 诊断和治疗解决方案，以提高慢性肾脏病患者的寿命。我们的总体目标是 通过犬尿氨酸途径(KP)确定色氨酸分解代谢在慢性肾脏病病理生理学中的作用 动脉硬化。我们的中心假设是色氨酸分解代谢犬尿酸(KA)导致 CKD动脉粥样硬化，而3-羟基邻氨基苯甲酸(3-HAA)可以改善这个问题。我们的 理论基础是，如果KP代谢物在CKD动脉粥样硬化中起因果作用，那么我们可以开发新的 减轻CKD人群心血管疾病负担的治疗策略和生物标记物。我们将测试我们的 通过追求以下具体目标来实现中心假设：1)论证循环和 巨噬细胞特异性KA，以及2)描述循环和巨噬细胞3-HAA的抗炎作用。 CKD动脉粥样硬化的发病机制。在目标1下，我们将描绘循环KA的影响，定义 巨噬细胞KA缺乏症在生物库人主动脉标本和CKD动脉粥样硬化中的作用 模型，并确定KA诱导的巨噬细胞分子机制，如芳烃和 细胞-膜G蛋白偶联受体35通路在CKD动脉粥样硬化发病机制中的作用 对于目标2，我们计划描绘循环中3-HAA的作用，确定巨噬细胞3-HAA的作用 使用生物库标本和CKD动脉粥样硬化模型，并鉴定3-HAA诱导的 巨噬细胞机制，如炎症小体激活在CKD动脉粥样硬化发病机制中的作用。这个 拟议的研究是创新的，因为它将CKD和CKD中的巨噬细胞炎症和代谢联系起来 皮损巨噬细胞色氨酸代谢与循环KP代谢物的作用 CKD患者的代谢谱分析和髓系特异性KP缺乏症的研究 动脉粥样硬化模型。这项拟议的研究意义重大，因为它将提供强有力的证据证明 色氨酸代谢在CKD动脉粥样硬化发病机制中的作用 发现有效的生物标记物和临床研究以预防CKD动脉粥样硬化中的心血管事件。

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.