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Role of the renal organic anion transporter OAT1 in metabolism and physiology

肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用

基本信息

批准号：
10645329
负责人：
SANJAY K NIGAM
金额：
$ 3.24万
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：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645329
关键词：
3-Dimensional ATP-Binding Cassette Transporters Antibiotic Therapy Antibiotics Antioxidants Attention Binding Biochemical Pathway Biological Assay Body Fluids Branched-Chain Amino Acids CCL21 gene Collection Computational Biology Data Diabetes Mellitus Diet Diet Modification Disease Disease model Docking Drug Transport Ensure FDA approved Fatty Acids Fatty acid glycerol esters Functional disorder Future Gene Expression Guidelines High Fat Diet Human In Vitro Insulin Resistance Interferometry Intestines Kidney Knock-out Knockout Mice Label Ligands Liver Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Metabolite Interaction Methods Modeling Mus Network-based Obesity Organic Anion Transporters Organoids Pathologic Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Physiological Physiology Play Publishing Radiolabeled Regulation Research Personnel Role Signaling Molecule Students Substrate Specificity Techniques Testing Time Tissues Validation Vitamins base design dietary genome-wide gut microbiome in silico in vivo induced pluripotent stem cell knockout animal metabolomics novel therapeutics reconstruction success transcriptomics uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Owing to new regulatory guidelines, the organic anion transporter (OAT1)--a transporter discovered by the PI's group (as NKT) and which is involved in the elimination of many common drugs--has received considerable attention. But nearly all the published studies continue to focus on common drugs rather than endogenous substrates of the transporter, which is highly conserved from an evolutionary standpoint. Metabolomics analysis of our Oat1 knockout mice (Oat1KO), as well as in vitro transport data, indicate that OAT1 is a major transporter of metabolites, signaling molecules, vitamins, gut microbiome products, and antioxidants. Our previous genome-scale metabolic reconstructions of altered metabolism of the Oat1KO mouse under normal dietary conditions enabled us to create the first multispecific "drug" transporter (OAT1)- centered metabolic network--which was further supported by considerable metabolomics and in vitro data. Many pathways (e.g., fatty acids, gut microbiome products, branched chain amino acids) in this largely validated network of ~150-200 metabolites are also known to be important in metabolic diseases such as diabetes, metabolic syndrome, obesity, and gut microbiome-associated illness. In this proposal: 1) We will use dietary modifications (e.g., high fat, branched chain amino acids) and antibiotic treatment of the Oat1 KO mice to define the role of Oat1 under conditions applicable to metabolic diseases. We will test the binding of metabolites revealed by metabolomics under the various dietary conditions (or disease models) using a high throughput unlabeled (BLI) assay to quantify the interaction of metabolites with OAT1; this information will be used to prioritize metabolites for subsequent uptake assays involving the use of radiolabeled compounds. 2) We will then use this information, together with gene expression data from the knockout tissues under various dietary conditions, to reconstruct a metabolic network for each of these dietary (pathological model) conditions- -using methods we have previously successfully used to create an "OAT1-centered metabolic network" under normal dietary conditions. Together, these studies will help define the unique roles of OAT1 in regulation of aberrant metabolism in these dysregulated metabolic states. Finally, we discuss how this information will set the stage for understanding aspects of drug-induced metabolic syndrome in patients taking OAT1- transported drugs. We have proven expertise in the necessary techniques and a team of world-class collaborators to ensure success.

项目总结/文摘

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease.

DOI：
10.3390/pharmaceutics13101720
发表时间：
2021-10-18
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Nigam AK;Ojha AA;Li JG;Shi D;Bhatnagar V;Nigam KB;Abagyan R;Nigam SK
通讯作者：
Nigam SK

SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo.

蝇肾脏系统中的SLC22转运蛋白调节体内对氧化应激的反应。

DOI：
10.3390/ijms222413407
发表时间：
2021-12-14
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Zhang P;Azad P;Engelhart DC;Haddad GG;Nigam SK
通讯作者：
Nigam SK

The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.

DOI：
10.1172/jci.insight.160437
发表时间：
2023-01-24
期刊：
JCI INSIGHT
影响因子：
8
作者：
Granados, Jeffry C.;Ermakov, Vladimir;Maity, Koustav;Vera, David R.;Chang, Geoffrey;Nigam, Sanjay K.
通讯作者：
Nigam, Sanjay K.