The Role of OAT1 in Uremia

OAT1 在尿毒症中的作用

基本信息

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
项目类别：
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

项目摘要

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.