The Role of OAT1 in Uremia

OAT1 在尿毒症中的作用

• 批准号: 9240444
• 负责人: SANJAY K NIGAM
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240444
• 关键词: Address; Adverse drug effect; Affect; Animal Model; Anions; Antibiotics; Antiviral Agents; Backcrossings; Behavior; Big Data; Biochemical Pathway; Biological Assay; Biology; Body Fluids; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Data; Data Set; Diabetic Nephropathy; Dialysis procedure; Disease; Disease model; Diuretics; Drug Transport; Epidemiologist; Epidemiology; Family; Functional disorder; Grant; Graph; Hand; Human; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Lead; Life; Ligands; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Mus; Nature; Nephrectomy; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Organic Anion Transport Protein 1; Organic Anion Transporters; Outcome; P-Glycoprotein; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phenotype; Physiological; Physiological Processes; Physiology; Play; Process; Proximal Kidney Tubules; Publishing; Rattus; Reaction; Renal Mass; Renal function; Research Personnel; Rodent; Role; Science; Statistical Data Interpretation; Syndrome; Systems Biology; Techniques; Testing; Tissues; Toxin; Translations; Uremia; Validation; Whole Organism; base; design; drug discovery; experimental study; genome-wide; improved; in vivo; metabolic phenotype; metabolomics; network models; novel therapeutics; pharmacophore; prototype; reconstruction; response; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT OAT1 (SLC22A6) is the prototypical kidney organic anion (PAH) transporter. It is responsible for the transport of many drugs (eg. antibiotics, diuretics, antivirals, NSAIDs) and toxins (organic mercurials). We identified the transporter (as NKT); we also first published the Oat1 knockout (Oat1KO) and phenotypes. Our recent data indicates that OAT1 is central to many systemic and proximal tubule metabolic processes. Oat1KO metabolomics data indicates OAT1 may be the key in vivo transporter of uremic toxins accumulating in renal insufficiency and chronic kidney disease (CKD). Altering OAT1 function and/or expression may ameliorate the metabolic changes in states of compromised renal function. We hypothesize that the “true” physiological role of OAT1 is as a central component of a larger metabolic network involved in normal physiological and pathophysiological processes, and OAT1 exerts a modulatory effect on metabolic diseases (eg. uremic syndrome) via this network. We will define the OAT1-centered network in detail. Specifically: 1) We will construct the OAT1-centered metabolic network through metabolic reconstruction of transcriptomics and metabolomics data from the Oat1KO (using the systems biology techniques described). We should be able to clearly delineate the pathways by which OAT1 regulates normal metabolism by: a) overlaying ligand-based pharmacophore models (in-hand) upon this preliminary reconstructed OAT1-centered network, and b) testing of “hits” in wet lab transport assays. 2) We will then determine what role the validated OAT1-centered metabolic network (and key pathways within it) plays in the metabolic alterations of renal insufficiency using rodent subtotal nephrectomy models and human CKD metabolomics data. We seek to build a very detailed, fully validated, network of >200 metabolites and reactions that makes predictions that can be evaluated in pathophysiological models and disease states. In response to previous criticisms, we have revised the proposal, particularly with respect to the disease model—and included an expert collaborator from the UCSD O’Brien Center to help with the studies and interpretation. Although the project was considered ambitious, we emphasize the huge amount of preliminary data and “in house” expertise. The team of investigators has expertise in transport, metabolism, network biology, epidemiology of kidney disease, animal models, and statistical analysis of large data sets. This project will thus produce a validated detailed map of OAT1-centered metabolism in normal physiology and a diseased state, possibly the first of its kind for any multispecific “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; they will also help predict how OAT1-transported drugs affect metabolism in kidney disease.

项目总结/摘要 OAT 1（SLC22A6）是原型肾脏有机阴离子（PAH）转运蛋白。它负责运输 许多药物（如抗生素、利尿剂、抗病毒药、非甾体抗炎药）和毒素（有机汞剂）。我们确定了 转运蛋白（作为NKT）;我们还首次发表了Oat1敲除（Oat1KO）和表型。我们最近的数据 表明OAT 1是许多全身和近端小管代谢过程的中心。Oat1KO 代谢组学数据表明，OAT 1可能是尿毒症毒素在肾组织中蓄积的关键体内转运蛋白。 肾功能不全和慢性肾病（CKD）。改变OAT 1功能和/或表达可改善 肾功能受损状态下的代谢变化。我们假设， OAT 1是一个更大的代谢网络的中心组成部分，参与正常的生理和 病理生理过程，并且OAT 1对代谢疾病（例如，尿毒症 综合症）通过这个网络。我们将详细定义以OAT1为中心的网络。具体来说：1）我们将 通过转录组学的代谢重建构建以OAT 1为中心的代谢网络， 来自Oat1KO的代谢组学数据（使用所述的系统生物学技术）。我们应该能够 清楚地描述了OAT 1通过以下方式调节正常代谢的途径：a）覆盖基于配体的 药效团模型（现有）在这个初步重建的OAT 1为中心的网络，和B）测试 在湿实验室运输分析中的"命中"。2)然后，我们将确定经验证的OAT1中心 代谢网络（以及其中的关键途径）在肾功能不全的代谢改变中起作用， 啮齿动物肾次全切除模型和人CKD代谢组学数据。我们试图建立一个非常详细的， 经过充分验证的，由超过200种代谢物和反应组成的网络，可以在 病理生理模型和疾病状态。为回应以往的批评，我们已修订 建议，特别是关于疾病模型-包括来自UCSD的专家合作者 奥布莱恩中心，以帮助研究和解释。虽然该项目被认为是雄心勃勃的，但我们 强调大量的初步数据和"内部"专业知识。调查小组已经 运输、代谢、网络生物学、肾脏疾病流行病学、动物模型和 大型数据集的统计分析。因此，该项目将生成以OAT1为中心的 在正常生理和疾病状态下的代谢，可能是任何多特异性"药物"的第一种 转运蛋白（Nigam，Nature Reviews Drug Discovery，2015）。这些研究可能会导致设计战略， 通过影响OAT1功能或表达改善CKD的代谢异常;它们也将有助于 预测OAT1转运药物如何影响肾脏疾病的代谢。