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: 10056622
• 负责人: EDWARD J KELLY
• 金额: $ 22.15万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056622
• 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; Diet; 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; 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.

项目摘要/摘要 CKDU（未知病因的CKD）主要发生在发展中国家，并且与生活和生活有关 在炎热的气候下在农业社区工作。在低收入中，治疗CKDU的成本无法实现 30天必需药物的工资最高为18天的国家。提议的风险因素是 CKDU是长期暴露于ochratoxin A（OTA），这是一种在谷物，豆类，干燥的谷物毒素的常见霉菌毒素 水果，葡萄酒，咖啡和茶。 OTA是几种动物物种中证明的肾癌，但是 由于缺乏适当的模型，包括肝 生物活化作为最终有毒部分的来源。 我们最近开发了肝>肾脏微生物生理系统（MPS），用于识别 与与 aristolochic酸介导的CKDU。原发性肝脏和肾细胞在恒定流动下培养 局部I/II/II酶和转运蛋白，这是对永生的细胞系的重大进展，迅速 失去酶表达和转运蛋白极化。此外，原发性肾脏近端小管细胞表现出 肾损伤生物标志物的强大和仿生分泌。 对于此提案，我们开发了一个创新的综合肝>肾脏> 在单个芯片上耦合并取消了肾脏的肾脏MPS。我们建议定义 绿毒素A和热应激引起的肾病，鉴定肾脏尾毒素涉及的转运蛋白 吸收和外排，并确定第一次期代谢在尾毒素A诱导的肾病中的作用。一个 更好地了解OTA诱导的肾脏损伤机制将支持风险评估的变化， 有关允许暴露水平的监管机构政策，并确定高风险的遗传风险因素 人群。