基于代谢组学和质谱成像研究色氨酸分解代谢在急性肾损伤中的作用机制

Acute kidney injury (AKI) is a common disorder and is associated with a high morbidity and mortality worldwide. However, the current measurements of AKI are neither sensitive nor specific, and the pathogenesis is still not completely understood. In our previous work, we found that tryptophan was down-regulated, and the downstream products kynurenine and kynurenate were significantly up-regulated in the urine of AKI patients. Thus, we speculate that tryptophan catabolism may play a vital role in AKI. In this study, 1) we will investigate the correlation between levels of tryptophan metabolites and subtype, severity and therapeutic evaluation of AKI using metabolomics approach on AKI patients and counterparts. 2) We will determine the tryptophan metabolites abundance and their spatial distribution in kidney by using tandem MS and MS imaging, characterizing the heterogeneity of kidney damage in AKI mouse model with different kidney sub-structural damage. 3) We will further investigate the role of aryl hydrocarbon receptor (AhR)-mediated trptophan-kynurenine axis in the pathogenesis of AKI, since kynurenate and kynurenine as ligands can active AhR. The study is helpful to reveal the pathogenesis of AKI, and will provide important evidences for evaluation of clinical diagnostics at early stage, therapy and prognostics effect of AKI.

急性肾损伤(AKI)，作为一种世界范围内患病率和致死率都很高的疾病，其病理生理机制尚不明确，临床早期诊断和治疗仍有很大困难。我们前期的代谢组学研究发现，AKI患者尿液中色氨酸下调，而分解产物犬尿酸等显著上调，提示色氨酸分解代谢在AKI发生发展中发挥重要作用。基于此，本项目拟开展如下工作：1）通过AKI患者和肾功能正常志愿者的代谢组学研究，明确色氨酸分解代谢与AKI种类、严重程度及干预效果的相关性；2）应用靶向代谢组学和质谱成像方法，探讨色氨酸及其代谢物在AKI模型小鼠（不同肾脏微区损伤）的体内水平和肾脏空间分布，验证色氨酸通路与肾脏组织空间异质性的相关性；3）聚焦于芳香烃受体（AhR），深入研究AhR介导色氨酸-犬尿酸代谢物调控AKI的作用机制。本研究的开展有助于进一步阐明AKI发生发展的病理机制，为临床上AKI的早期预测、治疗干预和预后评估提供参考依据和重要线索。

急性肾损伤（acute kidney injury, AKI）是一种高死亡率、发病率逐年增长、预后治疗费用高的临床疾病。重症住院患者发生AKI的死亡率更高，早期发现AKI、探索发生机制对于提高患者生存率和生活质量具有重要意义。本项目建立前瞻性重症患者AKI风险队列人群，联合应用非靶向和靶向代谢组学分析方法，验证色氨酸代谢是AKI发生的重要代谢紊乱通路，发现AKI发生进程中甲硫氨酸代谢、嘌呤代谢等通路发生紊乱，筛选到犬尿氨酸、吲哚乙酸和吲哚丙酸等指征AKI早期诊断的代谢标志物。基于万古霉素诱导的急性肾损伤（VI-AKI）小鼠模型，联合血清代谢组学和肾脏原位成像技术筛选到万古霉素诱导AKI的色氨酸代谢及脂质代谢紊乱，以及甘草酸（GA）可能通过调控肠道菌群相关的色氨酸代谢物发挥肾脏保护作用。