Development of rat liver 3D organoid methods to address genotoxicity screening

项目摘要 在简单的2D培养系统中研究细胞具有许多易于使用的优点， 能够在短时间内筛选许多条件，有针对性地添加或删除 对基因、蛋白质或其他成分的研究和对特定途径的重点研究 只代表少数几个人。然而，这种简单性也可能导致关键功能的丧失 总体上缺乏与整个有机体的相关性，特别是人类。为了努力 在培养皿中的细胞和人类之间弥合这一鸿沟，体外模型正在进行中 它模仿了整个器官的功能，也就是所谓的器官培养。 这些模型为研究高度复杂的多细胞系统提供了机会。 这将更像实际器官的反应，而不是在简单的 单层。我们的研究将建立一个大鼠肝细胞的三维生长模型。 格式化并将其与高效、高内容的分析平台配对，该平台将提供 有关DNA功能和细胞健康的信息。这些类型的模型的价值在于 对基础科学和更有针对性的研究工作，如人类 安全研究。工业用候选药物等化合物的安全性评估 化学品和消费品依赖于临床前测试模型来报告有用 关于人类安全的信息。基于细胞的模型做到这一点的能力通常是 当体外和体内系统与人类缺乏足够的相关性时受到挑战 条件。建议的3D器官模型可能会克服现有的限制和结果 成本更低，同时提供更好的信息。数据丰富的分析相结合 能够快速有效地评估体外动物来源的器官模型 代表着改进安全测试和创建将受益的工具的机会 许多其他依赖于体外系统的研究计划。

Project Summary Studying cells in simple 2D culture systems has many advantages with of ease of use, ability to screen many conditions in a short amount of time, targeted addition or deletion of genes, proteins or other components and focused study of specific pathways representing only a few. However, that simplicity can also lead to loss of key functions and an overall lack of relevancy to whole organisms, especially humans. In an effort to bridge this gap between cells in a dish and a human being, in vitro models are being developed that mimic the function of whole organs, so-called organotypic cultures. These models represent an opportunity to study highly complex, multicellular systems that will respond more like actual organs as opposed to cells grown in a simple monolayer. Our studies will develop a model of rat liver cells grown in a 3-dimensional format and pair that with an efficient, high-content analytical platform that will provide information on DNA function and cell health. The value of these types of models is significant for both basic science and more targeted research efforts such as human safety studies. Assessment of the safety of compounds like drug candidates, industrial chemicals and consumer products relies on preclinical test models to report useful information of human safety. The ability of cell-based models to do this is often challenged when the in vitro and in vivo systems lack sufficient relevancy to the human condition. The proposed 3D organ models may overcome existing limitations and result in lower costs while providing better information. The combination of data-rich assays that enable fast and efficient assessment of in vitro animal-derived organ models represents an opportunity to improve safety testing and create tools that will benefit numerous other research initiatives that rely on in vitro systems.