Tryptophan immune metabolism and vascular inflammation in CKD associated atherosclerosis

CKD相关动脉粥样硬化中色氨酸免疫代谢和血管炎症

• 批准号: 10687399
• 负责人: Anna Vachaparampil Mathew
• 金额: $ 44.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687399
• 关键词: Acids; Amino Acids; Anti-Inflammatory Agents; Aortic Diseases; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biological Markers; Blood Circulation; Blood Vessels; CASP1 gene; CXCR3 gene; Cardiovascular Diseases; Catabolism; Cell membrane; Cell surface; Chronic Kidney Failure; Clinical Research; Data; Diagnostic; Dialysis patients; Dioxygenases; Down-Regulation; Enzymes; Event; Experimental Models; Functional disorder; GPR35 gene; GTP-Binding Proteins; General Population; Goals; Health; Human; Immune; Inflammasome; Inflammation; Inflammatory; Knowledge; Kynurenic Acid; Kynurenine; Lesion; Life; Life Expectancy; Link; Longevity; Metabolic; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Nitric Oxide; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Platelet-Derived Growth Factor; Play; Population; Production; Public Health; Quinolinic Acid; Receptor Signaling; Renal dialysis; Renal function; Research; Role; Sampling; Specimen; Testing; Therapeutic; Tissues; Transferase; Tryptophan; Tryptophan Metabolism Pathway; United States National Institutes of Health; Up-Regulation; aryl hydrocarbons; burden of illness; cytokine; diagnostic strategy; disability; improved; indoleamine; innovation; interleukin-12 receptor; macrophage; mortality; novel therapeutic intervention; preservation; prevent; receptor; targeted biomarker; therapeutic target; vascular inflammation

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.

项目总结/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， CKD和透析患者的预期寿命减少到一般人的一半到三分之一， 人口然而，慢性肾脏病中加速性心血管疾病的发病机制尚不清楚， 目前可利用特定的治疗策略来减弱这种现象。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，以延长CKD患者的寿命。我们的总体目标是 通过犬尿氨酸途径（KP）确定色氨酸催化剂在CKD病理生理学中的作用 动脉粥样硬化我们的中心假设是色氨酸分解代谢物犬尿烯酸（KA）导致 CKD动脉粥样硬化，而3-羟基邻氨基苯甲酸（3-HAA）改善这一问题。我们 基本原理是，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 治疗策略和生物标志物，以减轻CKD人群中的CVD负担。我们将测试 通过追求以下具体目标：1）证明循环和 巨噬细胞特异性KA，和2）描绘循环和巨噬细胞3-HAA的抗炎作用， CKD动脉粥样硬化的发病机制。在目标1下，我们将描述循环KA的影响，定义 巨噬细胞KA缺乏在生物库人类主动脉标本和CKD动脉粥样硬化中的作用 模型，并确定KA诱导的巨噬细胞的分子机制，如激活芳烃和 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 关于目标2，我们计划描述循环3-HAA的作用，确定巨噬细胞3-HAA的作用， 使用生物库主动脉样品和CKD动脉粥样硬化模型，并鉴定3-HAA诱导的 巨噬细胞机制，如炎症体激活在CKD动脉粥样硬化的发病机制。的 拟议的研究是创新的，因为它将CKD中的巨噬细胞炎症和代谢联系起来， 描述了病变巨噬细胞色氨酸代谢与循环KP代谢物的贡献 通过质谱代谢谱分析和CKD中骨髓特异性KP缺乏研究CKD动脉粥样硬化 动脉粥样硬化模型。这项拟议中的研究意义重大，因为它将提供强有力的证据， 色氨酸代谢在CKD动脉粥样硬化发病机制中的作用，可能导致 发现经验证的生物标志物和临床研究，以预防CKD动脉粥样硬化中的CV事件。