The Role in OAT1 in Uremia

OAT1 在尿毒症中的作用

• 批准号: 10531107
• 负责人: SANJAY K NIGAM
• 金额: $ 62.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531107
• 关键词: Affect; Anions; Antibiotics; Antiviral Agents; Avena sativa; Bacterial Genes; Bile Acids; Binding Proteins; Biochemical Pathway; Blood; Brain; Chronic Kidney Failure; Citric Acid Cycle; Communication; Consequentialism; Data; Data Set; Disease; Disease model; Diuretics; Feces; Genes; Human; In Vitro; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lead; Life; Lipids; Liver; Maps; Mediating; Metabolic; Metabolism; Metagenomics; Methods; Microbe; Modeling; Mus; Nature; Nephrectomy; Non-Steroidal Anti-Inflammatory Agents; Organ; Organic Anion Transport Protein 1; Organic Anion Transporters; Organism; Paper; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Plasma; Proximal Kidney Tubules; Publishing; Renal function; Residual state; Rodent; Role; Sampling; Serum; Signal Transduction; Syndrome; System; Tissues; Toxic effect; Toxin; Tryptophan; Tryptophan Metabolism Pathway; Tubular formation; Uremia; Vitamins; Work; base; cofactor; design; differential expression; drug discovery; experience; genome sequencing; genome-wide; gut bacteria; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; host microbiota; improved; in vivo; lipid metabolism; metabolomics; microbial genome; microbiome; multi-scale modeling; novel; novel therapeutics; operation; reconstruction; remote sensing; small molecule; solute; theories; therapy design; transcriptomics; whole genome

OAT1 IN UREMIA PROJECT SUMMARY/ABSTRACT Organic anion transporter 1 (OAT1/SLC22A6), discovered by us (NKT), is the prototypical kidney organic anion (PAH) transporter responsible for the transport of many drugs (e.g., diuretics, antivirals, NSAIDs). Based on our in vivo studies of the Oat1 knockout mouse during the last project period and in vitro studies by us and others, OAT1 is now believed to be a central component of a proximal tubule sensing and elimination mechanism for gut microbe products and uremic toxins. Furthermore, recent data from our lab in rodents, as well as human studies by others, indicates that OAT1-dependent function is critical for residual kidney function in CKD. However, what is truly remarkable from our metabolomics and transcriptomics studies is the degree to which OAT1, which is almost exclusively expressed in the kidney, regulates systemic metabolism--beyond gut microbe products and uremic toxins. For example, it regulates many signaling lipids, citric acid cycle intermediates, bile acids, and vitamins/cofactors. Indeed, OAT1 may be the renal gene with the broadest effects on systemic metabolism. Although CKD is a multi-factorial disease, one of these factors is the metabolic consequence of the gradual loss of OAT1-dependent sensing and elimination as proximal tubule function declines. Thus, we hypothesize that, in CKD, the normal functioning of OAT1-mediated protein-bound metabolite sensing and signaling in the proximal tubule is severely disrupted--leading to major disruptions in small molecule metabolism and signaling. This is because of the endogenous role of OAT1 as a central component of a larger metabolic network involving gut microbe-derived metabolites, some of which participate in uremic toxicity in severe kidney disease but which also impact tryptophan and lipid metabolism as well as other metabolic processes. Using the latest approaches to integration of large omics datasets and a particularly novel multi-scale metabolic reconstruction approach (combining Recon3D with a genome-scale microbiome reconstruction), we will define the pathways in Oat1 KO mice under conditions in which: a) the gut microbiome is present or depleted; and b) kidney function is compromised. At the end, we will have fully analyzed combinations of Oat1 KO vs WT, healthy vs depleted gut microbiome, and sham operation vs 5/6 nephrectomy, as sampled in the serum, kidney, liver and feces. This will settle (in mice) the relative importance of each altered state on levels of uremic toxins, on biochemical pathways, and on overall multi-scale metabolic impact as determined by genome-scale metabolic reconstruction for each of the conditions. A portion of the omics data has already been obtained (KO effect, partial gut microbe effect). This project will thus produce a validated detailed map of OAT1-centered metabolism in normal physiology and in diseased states, possibly the first of its kind for any multi-specific “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.

燕麦1在尿毒症