The Role in OAT1 in Uremia

OAT1 在尿毒症中的作用

基本信息

批准号：
10684232
负责人：
SANJAY K NIGAM
金额：
$ 61.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684232
关键词：
Affect Anions Antibiotic Therapy Antibiotics Antiviral Agents Avena sativa Bacterial Genes Bile Acids Binding Proteins Biochemical Pathway Blood Brain Chronic Kidney Failure Citric Acid Cycle Communication Data Data Set Disease Disease model Diuretics Feces Genes Human In Vitro Kidney Kidney Diseases Knock-out Knockout Mice Life Lipids Liver Maps Mediating Metabolic Metabolism Metagenomics Methods Microbe Modeling Mus Nature Nephrectomy Non-Steroidal Anti-Inflammatory Agents Organ Organic Anion Transport Protein 1 Organic Anion Transporters Organism Paper Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Physiology Plasma Proximal Kidney Tubules Publishing Renal function Residual state Rodent Role Sampling Serum Signal Transduction Syndrome System Tissues Toxic effect Toxin Tryptophan Tryptophan Metabolism Pathway Tubular formation Uremia Vitamins Work cofactor design differential expression drug discovery experience genome sequencing genome-wide gut bacteria gut dysbiosis gut microbes gut microbiome gut microbiota host microbiota improved in vivo lipid metabolism metabolomics microbial genome microbiome multi-scale modeling novel novel therapeutics operation reconstruction remote sensing small molecule solute theories therapy design transcriptomics whole genome

项目摘要

OAT1 IN UREMIA PROJECT SUMMARY/ABSTRACT Organic anion transporter 1 (OAT1/SLC22A6), discovered by us (NKT), is the prototypical kidney organic anion (PAH) transporter responsible for the transport of many drugs (e.g., diuretics, antivirals, NSAIDs). Based on our in vivo studies of the Oat1 knockout mouse during the last project period and in vitro studies by us and others, OAT1 is now believed to be a central component of a proximal tubule sensing and elimination mechanism for gut microbe products and uremic toxins. Furthermore, recent data from our lab in rodents, as well as human studies by others, indicates that OAT1-dependent function is critical for residual kidney function in CKD. However, what is truly remarkable from our metabolomics and transcriptomics studies is the degree to which OAT1, which is almost exclusively expressed in the kidney, regulates systemic metabolism--beyond gut microbe products and uremic toxins. For example, it regulates many signaling lipids, citric acid cycle intermediates, bile acids, and vitamins/cofactors. Indeed, OAT1 may be the renal gene with the broadest effects on systemic metabolism. Although CKD is a multi-factorial disease, one of these factors is the metabolic consequence of the gradual loss of OAT1-dependent sensing and elimination as proximal tubule function declines. Thus, we hypothesize that, in CKD, the normal functioning of OAT1-mediated protein-bound metabolite sensing and signaling in the proximal tubule is severely disrupted--leading to major disruptions in small molecule metabolism and signaling. This is because of the endogenous role of OAT1 as a central component of a larger metabolic network involving gut microbe-derived metabolites, some of which participate in uremic toxicity in severe kidney disease but which also impact tryptophan and lipid metabolism as well as other metabolic processes. Using the latest approaches to integration of large omics datasets and a particularly novel multi-scale metabolic reconstruction approach (combining Recon3D with a genome-scale microbiome reconstruction), we will define the pathways in Oat1 KO mice under conditions in which: a) the gut microbiome is present or depleted; and b) kidney function is compromised. At the end, we will have fully analyzed combinations of Oat1 KO vs WT, healthy vs depleted gut microbiome, and sham operation vs 5/6 nephrectomy, as sampled in the serum, kidney, liver and feces. This will settle (in mice) the relative importance of each altered state on levels of uremic toxins, on biochemical pathways, and on overall multi-scale metabolic impact as determined by genome-scale metabolic reconstruction for each of the conditions. A portion of the omics data has already been obtained (KO effect, partial gut microbe effect). This project will thus produce a validated detailed map of OAT1-centered metabolism in normal physiology and in diseased states, possibly the first of its kind for any multi-specific “drug” transporter (Nigam, Nature Reviews Drug Discovery, 2015). The studies could lead to design of strategies for improving the metabolic abnormalities in CKD by affecting OAT1 function or expression.

OAT1在尿毒症中项目摘要/摘要有机阴离子转运蛋白1（OAT1/SLC22A6），美国（NKT）是原型肾脏有机阴离子（PAH）负责许多药物运输的转运蛋白（例如利尿剂，抗病毒药，NSAID）。基于我们在最后一个项目期间对OAT1敲除小鼠的体内研究以及我们和我们的体外研究其他人，现在据信OAT1是近端tubelle感应和紧急的核心组成部分肠道微生物产物和尿毒症毒素的机制。此外，我们实验室实验室的最新数据是以及其他人的人类研究，表明OAT1依赖性功能对于残留肾脏功能至关重要在CKD中。但是，从我们的代谢组学和转录组学研究中真正引人注目的是几乎在肾脏中几乎完全表达的OAT1调节系统性代谢微生物产物和尿毒症毒素。例如，它调节许多信号脂质，柠檬酸循环中间体，胆汁酸和维生素/辅助因子。确实，OAT1可能是最广泛的肾脏基因对系统性代谢的影响。尽管CKD是一种多因素疾病，但这些因素之一是 OAT1依赖性感应和消除的年级损失作为近端管的代谢结果功能下降。这就是我们假设，在CKD中，OAT1介导的蛋白质结合的正常功能近端小管中的代谢物敏感性和信号传导严重破坏 - 主要破坏小分子代谢和信号传导。这是因为OAT1作为中央的内源性作用涉及肠道微生物衍生代谢物的较大代谢网络的组成部分，其中一些参与在严重肾脏疾病中尿毒症毒性中，这也影响色氨酸和脂质代谢以及其他代谢过程。使用最新方法来集成大型OMIC数据集和特别是新型的多尺度代谢重建方法（将Recon3D与基因组规模相结合微生物组重建），我们将在OAT1 KO小鼠中定义途径，在：a）肠微生物组被提出或耗尽； b）肾功能受到损害。最后，我们将完全拥有分析了OAT1 KO与WT的组合，健康与肠道微生物组的加深和假手术与5/6 肾切除术，如在血清，肾脏，肝脏和粪便中取样。这将（在小鼠中）相对重要每种改变状态的尿毒症毒素水平，生化途径以及总体多尺度代谢的状态由每个条件的基因组规模的代谢重建确定的影响。一部分 OMICS数据已经获得（KO效应，部分肠道微生物效应）。因此，这个项目将产生一个经过验证的正常生理和患病状态中OAT1中心代谢的详细图对于任何多个特异性“药物”运输蛋白的第一个（Nigam，自然评论药物发现，2015年）。研究可能导致设计通过影响OAT1来改善CKD代谢异常的策略功能或表达。