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

• 批准号: 10363049
• 负责人: Thomas Neumann
• 金额: $ 87.61万
• 依托单位: NORTIS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363049
• 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

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.

项目摘要 通过食物，家用产品，药物和 环境。肾脏特别容易受到化学损伤。药物诱导的肾毒性是主要的 在严重急性肾衰竭病例中，有25％的健康关注。肾毒性也是 药物开发中的重大问题；这是该过程后期消耗的主要原因，占19％ III期失败的临床试验。最先进的动物模型和用于预测的体外工具的局限性 人类肾毒性是充分认可的，这激发了高级3D体外的发展 人类组织和器官的模型，所谓的器官片系统（OOC）或微生物生理系统 （MPS）。尽管基于人类的MP的进展很快，但MPS数据之间仍然存在翻译差距 和体内数据。因此，将基于动物MP的观察结果与体内动物数据进行比较将告知 我们将人类国会议员发现转化为临床医学的能力。 这项快速拨款应用程序提出了两只动物的肾脏近端小管（KPT）MPS的发展 经常用于肾脏毒性筛查的物种：大鼠和狗。一旦成功发展， 经过验证和商业化的KPT-MP将作为化学毒性筛查的重要新工具 和药物开发，允许通过体内动物数据，人类 - 基于MPS数据和临床结果。它也有可能替代一些动物测试 减少活动物在临床前测试中的使用。 该项目的第一阶段旨在建立大鼠和狗的强大的KPT-MPS模型。该项目将利用 诺蒂斯MPS平台和建立人类基于人类的KPT-的预先建立的协议 - 国会议员。 I阶段/AIM 1将证明来自大鼠和狗的近端小管细胞可行，结构上可行 完整的近端小管，这些小管在暴露于化合物时表现出应力反应 对体内的KPT有毒（I/AIM 2阶段2）。至少两个中的至少一个可行性要求 在项目发展之前的物种。第二阶段将着重于优化大鼠和或狗KPT- MPS原型和开发用于测试潜在肾毒性化合物的测定法（II阶段/AIM 1）。为了 这些努力我们将利用由注射塑料的热塑性材料制成的新的微流体芯片，该芯片 是为人类基于人类的KPT-MP开发的。在II阶段/AIM 2期间，由五个具有已发表的化合物组成的面板 大鼠，狗和人类的物种特异性肾毒性将在KPT-MP中进行测试，以建立目标 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是证明 Rat/Dog KPT-MPS可以作为插头和播放预种植的产品运送给未来的客户。