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：
10086753
负责人：
Thomas Neumann
金额：
$ 25.21万
依托单位：
NORTIS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10086753
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 Structure 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.

项目概要人类不断通过食品、家用产品、药品和环境接触各种化学物质。环境。肾脏特别容易受到化学损伤；药物引起的肾毒性是主要的 25% 的严重急性肾衰竭病例是由健康问题造成的。肾毒性也是药物开发中的重大问题；这是流程后期人员流失的主要原因，占 19% 失败的 III 期临床试验。最先进的动物模型和体外预测工具的局限性人类肾毒性已得到广泛认可，这引发了先进 3D 体外技术的发展人体组织和器官模型，即所谓的器官芯片系统（OOC）或微生理系统（MPS）。虽然基于人的 MPS 进展迅速，但 MPS 数据之间仍存在转化差距和体内数据。因此，将基于动物的 MPS 观察结果与体内动物数据进行比较将提供信息我们将人类 MPS 研究结果转化为临床医学的能力。该快速拨款申请提议从两种动物身上开发肾近端小管 (KPT) MPS 经常用于肾毒性筛查的物种：大鼠和狗。一旦研发成功，经过验证并商业化后，KPT-MPS 将成为化学毒性筛查的重要新工具和药物开发，允许将基于动物的 MPS 数据与体内动物数据、人类数据进行交叉引用基于 MPS 数据和临床结果。它还有可能取代一些动物测试，显着减少临床前测试中活体动物的使用。该项目第一阶段旨在建立大鼠和狗的稳健 KPT-MPS 模型。该项目将利用商用 Nortis MPS 平台和预先制定的协议，用于创建基于人类的 KPT- MPS。 I/AIM 1 期将证明来自大鼠和狗的近端小管细胞形成有活力且结构良好的细胞。完整的近端小管，并且这些小管在暴露于以下化合物时表现出应激反应对体内 KPT 有毒（I/AIM 2 期）。可行性要求将至少在两者之一中确定项目进入第二阶段之前的物种。第二阶段将重点优化大鼠和/或狗 KPT- MPS 原型和开发用于测试潜在肾毒性化合物的检测方法（II 期/AIM 1 期）。为了在这些努力中，我们将利用一种由注射成型热塑性材料制成的新型微流控芯片，是为基于人类的 KPT-MPS 开发的。在 II/AIM 2 阶段期间，一组五种化合物已发表将在 KPT-MPS 中测试大鼠、狗和人类的物种特异性肾毒性，目的是确定 KPT-MPS 数据与所有三个物种的体内数据之间的相关性。第二阶段/AIM 3 旨在证明大鼠/狗 KPT-MPS 可以作为即插即用的预播种产品运送给未来的客户。