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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OAT 1 项目总结/摘要我们（NKT）发现的有机阴离子转运蛋白1（OAT 1/SLC 22 A6）是肾脏有机阴离子的原型 (PAH)负责运输许多药物的转运蛋白（例如，利尿剂、抗病毒药、NSAID）。基于我们在最后一个项目期间对Oat 1敲除小鼠的体内研究和我们的体外研究，其他人，OAT 1现在被认为是近端小管感知和消除的中心成分肠道微生物产物和尿毒症毒素的机制。此外，我们实验室在啮齿动物中的最新数据，以及其他人的人体研究表明，OAT 1依赖性功能对残余肾功能至关重要在CKD中。然而，我们的代谢组学和转录组学研究真正值得注意的是，其中OAT 1几乎只在肾脏中表达，调节肠道以外的全身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/辅因子。事实上，OAT 1可能是最广泛的肾脏基因，对全身代谢的影响虽然CKD是一种多因素疾病，但其中一个因素是作为近端小管，OAT 1依赖性感知和消除逐渐丧失的代谢结果功能下降。因此，我们假设，在CKD中，OAT 1介导的蛋白结合的正常功能，近端小管中的代谢物传感和信号传导被严重破坏-导致小分子代谢和信号传导。这是因为OAT 1作为中枢神经系统的内源性作用。一个更大的代谢网络的组成部分，涉及肠道微生物衍生的代谢物，其中一些参与在严重肾脏疾病中尿毒症毒性，但也影响色氨酸和脂质代谢，其他代谢过程。使用最新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（将Recon 3D与基因组尺度相结合微生物组重建），我们将在以下条件下定义Oat 1 KO小鼠中的途径：a）肠道微生物组存在或耗尽;和B）肾功能受损。最后，我们将充分分析了Oat 1 KO与WT、健康与耗尽的肠道微生物组以及假手术与5/6的组合肾切除术，如在血清、肾、肝和粪便中取样。这将解决（在小鼠）的相对重要性每种改变的状态对尿毒症毒素水平、生化途径和整体多尺度代谢的影响由每种条件的基因组规模代谢重建确定的影响。的一部分已经获得了组学数据（KO效应、部分肠道微生物效应）。该项目将产生一个在正常生理状态和疾病状态下，以OAT 1为中心的代谢的经验证的详细图谱，首次用于任何多特异性“药物”转运蛋白（Nigam，Nature Reviews Drug Discovery，2015）。的研究可能导致设计通过影响OAT 1改善CKD代谢异常的策略功能或表达。