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/母基金摘要R01GM132932 (请参阅研究计划中多样性补充的项目摘要/摘要) 由于新的监管指南，有机阴离子转运体(OAT1)--一种被PI发现的转运体 小组(作为NKT)，并参与消除许多常见药物--收到了相当大的 请注意。但几乎所有已发表的研究都继续关注普通药物，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基因敲除小鼠(Oat1KO)的分析以及体外转运数据表明，OAT1是主要的 代谢物、信号分子、维生素、肠道微生物产物和抗氧化剂的运输者。我们的 Oat1KO小鼠在正常情况下代谢改变的先前基因组规模代谢重建 饮食条件使我们能够创造出第一个以代谢为中心的多特异性药物转运体(OAT1) 网络--这进一步得到了相当多的代谢组学和体外数据的支持。许多路径(例如， 脂肪酸、肠道微生物组产品、支链氨基酸)在这个由~150- 已知的200种代谢物对糖尿病、代谢综合征、 肥胖和肠道微生物群相关疾病。在这项建议中：1)我们将使用饮食调整(例如，高 脂肪、支链氨基酸)和抗生素治疗Oat1 KO小鼠以确定Oat1在 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，使用高通量无标记(BLI)分析 量化代谢物与OAT1的相互作用；这一信息将用于确定代谢物的优先顺序 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， 结合不同饮食条件下基因敲除组织的基因表达数据，重建 每种饮食(病理模型)条件下的代谢网络--使用我们之前的方法 成功地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在调节这些患者异常代谢方面的独特作用 代谢状态失调。最后，我们将讨论这些信息将如何为理解 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 具备必要技术的专业知识和世界级的合作者团队以确保成功。