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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.

尿毒症中的OAT1 项目摘要/摘要有机阴离子转运蛋白1(OAT1/SLC22A6)是美国(NKT)发现的肾脏有机阴离子转运蛋白。 (PAH)负责许多药物(如利尿剂、抗病毒药物、非甾体抗炎药)运输的运输者。基于我们在上一个项目期间对Oat1基因敲除小鼠的体内研究，以及我们和其他的，OAT1现在被认为是近端小管感知和消除的中心组成部分肠道微生物产物和尿毒症毒素的作用机制。此外，我们实验室最近在啮齿动物上的数据，如和其他人的人类研究一样，表明OAT1依赖的功能对残余肾功能至关重要在CKD中。然而，从我们的代谢组学和转录组学研究中真正值得注意的是，哪种OAT1几乎只在肾脏中表达，它调节全身代谢--超越肠道微生物产品和尿毒症毒素。例如，它调节许多信号脂类，柠檬酸循环中间体、胆汁酸和维生素/辅因子。事实上，OAT1可能是肾脏基因中最广泛的对全身代谢的影响。尽管慢性肾脏病是一种多因素疾病，但其中一个因素是作为近端小管的OAT1依赖感觉和消除的逐渐丧失的代谢后果功能下降。因此，我们假设，在慢性肾脏病中，OAT1介导的蛋白结合的正常功能近端小管的代谢物感知和信号严重中断--导致小分子代谢和信号传递。这是因为OAT1作为中枢的内源性作用。更大代谢网络的组成部分，涉及肠道微生物衍生的代谢物，其中一些参与严重肾脏疾病的尿毒症毒性，但也影响色氨酸和脂代谢以及其他代谢过程。使用最新的方法集成大型组学数据集和特别是新颖的多尺度代谢重建方法(结合了RECOR3D和基因组尺度微生物组重建)，我们将定义Oat1 KO小鼠在以下条件下的途径：a)肠道微生物组存在或耗尽；以及b)肾功能受损。到最后，我们将完全拥有分析了燕麦1KO与WT、健康与耗尽肠道微生物群以及假手术与5/6的组合肾切除，从血清、肾脏、肝脏和粪便中取样。这将(在老鼠身上)确定相对重要性尿毒症毒素水平、生化途径和整体多尺度代谢的每种改变状态通过对每种情况进行基因组规模的新陈代谢重建来确定影响。其中一部分是已经获得了组学数据(KO效应、部分肠道微生物效应)。因此，该项目将产生一个经过验证的正常生理和疾病状态下以OAT1为中心的代谢的详细图，可能是对于任何多具体的“药物”运输者来说，这是第一次(Nigam，《自然评论药物发现》，2015)。这个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。