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

• 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
• 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

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/父级授予R01GM132932的摘要 （请参阅项目摘要/摘要有关研究计划中多样性的补充） 由于新的调节指南，有机阴离子转运蛋白（OAT1） - PI发现的转运蛋白 组（作为NKT），并且参与消除许多常见药物 - 收到了相当大的 注意力。但是，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 从进化的角度来看，转运蛋白的底物是高度保守的。代谢组学 OAT1敲除小鼠（OAT1KO）以及体外传输数据的分析表明OAT1是主要的 代谢物，信号分子，维生素，肠道微生物组产物和抗氧化剂的转运蛋白。我们的 在正常下，OAT1KO小鼠的代谢改变的先前基因组规模的代谢重建 饮食条件使我们能够创建第一个多种特异性“药物”转运蛋白（OAT1） - 中心代谢 网络 - 由大量代谢组学和体外数据进一步支持。许多途径（例如， 脂肪酸，肠道微生物组产物，分支链氨基酸）在这个大量验证的〜150-的网络中 已知200个代谢产物在糖尿病，代谢综合征等代谢疾病中很重要 肥胖和肠道微生物组相关的疾病。在此提案中：1）我们将使用饮食修饰（例如，高 OAT1 KO小鼠的脂肪，分支链氨基酸）和抗生素治疗，以定义OAT1的作用 适用于代谢疾病的疾病。我们将测试由代谢组学揭示的代谢产物的结合 在各种饮食条件（或疾病模型）下，使用高通量未标记的（BLI）测定法 量化代谢物与OAT1的相互作用；此信息将用于确定代谢物的优先级 随后的摄取分析涉及使用放射性标记化合物。 2）然后我们将使用此信息， 以及来自各种饮食条件下基因敲除组织的基因表达数据，重建A 这些饮食（病理模型）条件中的每一种都使用的代谢网络，我们以前拥有 在正常饮食条件下成功地用于创建“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，我们讨论这些信息将如何为理解奠定基础 服用OAT1转运药物的患者中药物诱导的代谢综合征的方面。我们已经证明了 必要技术和世界一流合作者团队的专业知识，以确保成功。