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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要心血管疾病（CVD）是慢性肾脏疾病（CKD）的发病率和死亡率的主要原因，将CKD和透析患者的预期寿命降低到大约一半至三分之一的一半人口。但是，CKD中CVD加速的发病机理尚未清楚地理解，否目前可以使用特定的治疗策略来减轻这种现象。我们的长期目标是了解加速动脉粥样硬化的背后的免疫代谢机制，以发展改善CKD患者寿命的诊断和治疗解决方案。我们的总体目标是通过Kynurenine途径（KP）在CKD的病理生理学中定义色氨酸分解代谢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kynurenic酸（KA）引起的 CKD动脉粥样硬化，而3-羟基蒽（3-HAA）可以改善此问题。我们的理由是，如果KP代谢物在CKD动脉粥样硬化中起因果作用，那么我们可以发展新的治疗策略和生物标志物可以减轻CKD人群中CVD负担。我们将测试我们的通过追求以下具体目的：1）证明循环和巨噬细胞特异性KA和2）描述循环和巨噬细胞3-HAA在 CKD动脉粥样硬化的发病机理。在AIM 1下，我们将描述循环KA的效果，定义巨噬细胞KA缺乏症的作用在生物储备的人主动脉标本和CKD动脉粥样硬化中模型，并确定KA诱导的巨噬细胞分子机制，例如芳基烃和 CKD动脉粥样硬化发病机理中细胞膜G蛋白偶联受体35途径。关于目标2，我们计划描述循环3-HAA的效果，定义巨噬细胞3-HAA的作用使用Bio-Bank的主动脉样本和CKD动脉粥样硬化模型，并识别3-HAA诱导的巨噬细胞机制在CKD动脉粥样硬化的发病机理中的炎性体激活。这拟议的研究具有创新性，因为它与CKD和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的贡献与循环KP代谢物的贡献在CKD动脉粥样硬化中，通过质谱代谢分析和CKD中的粒细胞特异性KP缺乏症动脉粥样硬化模型。拟议的研究很重要，因为它将提供有力的证据色氨酸代谢在CKD动脉粥样硬化的发病机理中的机械作用，可能导致发现了经过验证的生物标志物和临床研究，以防止CKD动脉粥样硬化中的CV事件。