CKDu and Ochratoxin-A: risk assessment studies in a microphysiological system

CKDu 和赭曲霉毒素-A：微生理系统中的风险评估研究

• 批准号: 10197129
• 负责人: EDWARD J KELLY
• 金额: $ 18.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197129
• 关键词: 3-Dimensional; Active Biological Transport; Acute Renal Failure with Renal Papillary Necrosis; Animals; Apical; Aristolochic Acids; Biological Markers; Biological Models; Biomimetics; Carcinogens; Carrier Proteins; Cell Line; Cells; Cereals; Chemicals; Chronic; Chronic Kidney Failure; Coffee; Coupled; Development; Dose; Drug Metabolic Detoxication; Engineering; Enzymes; Etiology; Exhibits; Exposure to; Food; Fruit; Grain; Hazard Identification; Heat Stress Disorders; Hepatic; Hepatocyte; Human; Individual; Ingestion; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kinetics; Link; Liver; Measures; Mediating; Membrane; Metabolism; Microfluidics; Modeling; Molecular Profiling; Mycotoxins; No-Observed-Adverse-Effect Level; Occupational; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Policies; Population; Prevention; Property; Proximal Kidney Tubules; Public Health; Risk Assessment; Risk Factors; Role; Series; Source; Support System; Tea; Transport Process; Wages; Wine; agricultural community; base; bean; biophysical properties; carcinogenicity; cell immortalization; cost; dietary; exposure route; gene environment interaction; genetic risk factor; global health; high risk population; hot climate; human tissue; innovation; insight; kidney cell; liver metabolism; low income country; microphysiology system; nephrotoxicity; ochratoxin A; response; socioeconomics; transport inhibitor; uptake

Project Summary/Abstract CKDu (CKD of unknown etiology) occurs primarily in the developing world, and is associated with living and working in agricultural communities in hot climates. The cost of treating CKDu is unattainable in low-income countries, where 30 days of essential medications can cost up to 18 days wages. One proposed risk factor of CKDu is chronic exposure to Ochratoxin A (OTA), a common mycotoxin found in cereal grains, beans, dried fruits, wine, coffee, and tea. OTA is a demonstrated renal carcinogen in several animal species, however hazard identification in humans has been elusive due to the lack of adequate models that include hepatic bioactivation as a source of the ultimate toxic moiety. We have recently developed a coupled liver>kidney microphysiologic system (MPS) that was used to identify the specific hepatic enzymes, renal transporters, and intermediate chemical metabolites associated with aristolochic acid mediated CKDu. Cultured under constant flow, primary liver and kidney cells demonstrated localized phase-I/II enzymes and transporters, a significant advance over immortalized cell lines that rapidly lose enzyme expression and transporter polarization. In addition, primary kidney proximal tubule cells exhibited robust and biomimetic secretion of biomarkers of kidney injury. For this proposal, we have developed an innovative integrated liver>kidney MPS that incorporates both a coupled and uncoupled kidney MPS on a single chip. We propose to define the dose-response relationships of ochratoxin A and heat stress-induced nephropathy, identify the transport proteins involved in renal ochratoxin A uptake and efflux, and determine the role of first pass metabolism in ochratoxin A-induced nephropathy. A better understanding of the mechanisms of OTA-induced kidney injury will support changes in risk assessment, regulatory agency policies on allowable exposure levels, and determination of genetic risk factors in high-risk populations.

项目总结/摘要 CKDu（病因不明的CKD）主要发生在发展中国家，与生活和 在炎热气候下的农业社区工作。治疗CKDu的费用在低收入国家是无法达到的。 在一些国家，30天的基本药物费用可能高达18天的工资。一个拟议的风险因素是 CKDu是慢性暴露于赭曲霉毒素A（OTA），一种常见的真菌毒素，存在于谷物，豆类，干 水果、葡萄酒、咖啡和茶。然而，OTA在几种动物中是一种已证实的肾脏致癌物， 由于缺乏适当的模型，包括肝脏， 生物活化作为最终毒性部分的来源。 我们最近开发了一个耦合的肝脏>肾脏微生理系统（MPS），用于识别 特异性肝酶、肾转运蛋白和与之相关的中间化学代谢物 马兜铃酸介导CKDu。在恒定流下培养，原代肝和肾细胞显示 本地化的I/II相酶和转运蛋白，这是一个重大的进步，超过永生化细胞系， 失去酶表达和转运蛋白极化。此外，原代肾近曲小管细胞表现出 肾损伤生物标志物的稳健和仿生分泌。 对于该提案，我们开发了一种创新的集成肝脏>肾脏MPS， 在单个芯片上的偶联和非偶联肾MPS。我们建议定义的剂量反应关系 探讨赭曲霉毒素A与热应激性肾病的关系，确定参与肾赭曲霉毒素转运的蛋白质 A摄取和流出，并确定首过代谢在赭曲霉毒素A诱导的肾病中的作用。一 更好地理解OTA诱导的肾损伤机制将支持风险评估的变化， 监管机构关于允许暴露水平的政策，以及高风险人群中遗传风险因素的确定 人口。