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Rat and Canine Microphysiological Systems of the Kidney Proximal Tubule for Chemical Toxicity Screening

用于化学毒性筛查的大鼠和犬肾近端小管微生理系统

基本信息

批准号：
10405579
负责人：
Thomas Neumann
金额：
$ 80.36万
依托单位：
NORTIS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-14 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405579
关键词：
3-Dimensional Accounting Acute Kidney Failure Advanced Development American Animal Model Animal Testing Animals Apical Applications Grants Back Biological Assay Biological Models Canis familiaris Cell Culture System Cell Culture Techniques Cell Survival Cells Chemicals Clinical Clinical Medicine Data Devices Environment Exhibits Experimental Animal Model Exposure to Food Future Genes Goals Harvest Health Hepatocyte Household Products Human In Vitro Inflammation Injections Injury Injury to Kidney Kidney Laboratories Laboratory culture Lipids Location Medicine Microfluidic Microchips Microfluidics Modeling Molds Organ Outcome Performance Pharmaceutical Preparations Phase Phase III Clinical Trials Play Poison Polymyxin B Preclinical Testing Process Protocols documentation Proximal Kidney Tubules Publishing Rattus Regulation Running Seeds Shipping Ships Site Stains System Technology Testing Time Toxic effect Toxicology Translating Up-Regulation Variant animal data base biological adaptation to stress design drug development experience experimental study hazard human model human tissue in vitro Model in vivo kidney cell microphysiology system nephrogenesis nephrotoxicity organ on a chip performance tests predictive tools prototype rat KIM-1 protein response to injury sample collection screening tool toxicant

项目摘要

Project Summary Humans are constantly exposed to a variety of chemicals via food, household products, medicines, and the environment. The kidney is particularly susceptible to chemical damage; drug-induced nephrotoxicity is a major health concern that contributes to 25% of all cases of severe acute kidney failure. Nephrotoxicity is also a significant problem in drug development; it is a major cause of attrition late in the process, accounting for 19% of failed Phase III clinical trials. The limitations of state-of-the-art animal models and in vitro tools for predicting human nephrotoxicity are well acknowledged, which has sparked the development of advanced 3D in vitro models of human tissues and organs, so called organ-on-chip systems (OOC) or microphysiological systems (MPS). While progress with human-based MPS has been rapid, a translational gap remains between MPS data and in vivo data. Therefore, comparing observations from animal-based MPS to in vivo animal data will inform our ability to translate human MPS findings to clinical medicine. This fast-track grant application proposes the development of kidney proximal tubule (KPT) MPS from two animal species that are frequently used in kidney toxicity screening: rat and dog. Once successfully developed, validated, and commercialized, the KPT-MPS will serve as an important new tool in chemical toxicity screening and drug development, allowing cross-referencing animal-based MPS data with in vivo animal data, human- based MPS data and clinical outcomes. It also has the potential to replace some animal testing, significantly reducing the use of live animals in preclinical testing. Phase I of the project is designed to establish robust KPT-MPS models from rat and dog. The project will leverage the commercially available Nortis MPS platform and pre-established protocols for creating human based KPT- MPS. Phase I/AIM 1 will demonstrate that proximal tubule cells from rat and dog form viable and structurally complete proximal tubules and that these tubules exhibit a stress response when exposed to compounds that are toxic to KPTs in vivo (Phase I/AIM 2). Feasibility requirements will be established in at least one of the two species before the project progresses into Phase II. Phase II will focus on optimizing the rat and or dog KPT- MPS prototypes and on developing assays for testing potentially nephrotoxic compounds (Phase II/AIM 1). For these efforts we will leverage a new microfluidic chip made of an injection-molded thermoplastic material that was developed for a human-based KPT-MPS. During Phase II/AIM 2, a panel of five compounds with published species-specific nephrotoxicity for rat, dog, and human will be tested in the KPT-MPS with the goal to establish correlation between KPT-MPS data and in vivo data in all three species. Phase II/AIM 3 is to demonstrate that rat/dog KPT-MPSs can be shipped to future customers as a plug & play pre-seeded product.

项目总结