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：
10224587
负责人：
SANJAY K NIGAM
金额：
$ 4.52万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224587
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 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 parent grant reconstruction success transcriptomics uptake

项目摘要

PROJECT SUMMARY/ABSTRACT OF PARENT GRANT R01GM132932 (Please see project summary/abstract for Diversity Supplement in Research Plan) 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.

项目摘要/家长补助金摘要 R01GM132932 （研究计划中的多样性补充请参阅项目摘要/摘要）由于新的监管指南，PI 发现的有机阴离子转运蛋白 (OAT1) 团体（如 NKT）并参与消除许多常见药物 - 已收到相当多的注意力。但几乎所有已发表的研究都继续关注常见药物而不是内源性药物转运蛋白的底物，从进化的角度来看是高度保守的。代谢组学对我们的 Oat1 敲除小鼠 (Oat1KO) 的分析以及体外转运数据表明，OAT1 是一个主要的代谢物、信号分子、维生素、肠道微生物组产品和抗氧化剂的转运蛋白。我们的先前对 Oat1KO 小鼠正常情况下代谢改变的基因组规模代谢重建饮食条件使我们能够创建第一个以多特异性“药物”转运蛋白（OAT1）为中心的代谢网络——大量代谢组学和体外数据进一步支持了这一网络。许多途径（例如，脂肪酸、肠道微生物组产品、支链氨基酸）在这个经过广泛验证的约 150- 200 种代谢物也被认为对糖尿病、代谢综合征、肥胖和肠道微生物相关疾病。在此提案中：1）我们将采用饮食调整（例如，高对 Oat1 KO 小鼠进行抗生素治疗，以确定 Oat1 在以下情况下的作用：适用于代谢性疾病的条件。我们将测试代谢组学揭示的代谢物的结合在各种饮食条件（或疾病模型）下，使用高通量未标记（BLI）测定来量化代谢物与 OAT1 的相互作用；该信息将用于确定代谢物的优先顺序随后的吸收测定涉及使用放射性标记化合物。 2）然后我们将使用这些信息，结合不同饮食条件下敲除组织的基因表达数据，重建每种饮食（病理模型）条件的代谢网络 - 使用我们之前的方法成功用于在正常饮食条件下创建“以OAT1为中心的代谢网络”。一起，这些研究将有助于确定 OAT1 在调节这些疾病中的异常代谢中的独特作用。代谢状态失调。最后，我们讨论这些信息如何为理解奠定基础服用 OAT1 转运药物的患者中药物诱发的代谢综合征的各个方面。我们已经证明必要技术方面的专业知识和世界一流的合作者团队可确保成功。