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

开发大鼠肝脏 3D 类器官方法来解决遗传毒性筛查

基本信息

批准号：
10075486
负责人：
Jeffrey C Bemis
金额：
$ 17.66万
依托单位：
LITRON LABORATORIES, LTD.
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：
2020-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10075486
关键词：
3-Dimensional Address Animal Model Animals Basic Science Biological Assay Biological Markers Biological Sciences Cell Culture System Cell Culture Techniques Cell Nucleus Cells Characteristics Chemicals Companions Complex Cytochrome P450 Cytolysis DNA DNA Damage DNA Double Strand Break DNA Markers Data Development Discipline Epitopes Event Flow Cytometry Funding Future Gene Deletion Gene Proteins Growth Health Hepatocyte Human In Vitro Industrialization Investigation Label Laboratories Lead Life Liver Mediator of activation protein Metabolic Activation Metabolism Methodology Methods Modeling Mutagens Nuclear Organ Organ Model Organism Organoids Pathway interactions Phase Physiological Physiology Positioning Attribute Preclinical Testing Procedures Process Protocols documentation Rattus Reagent Reporting Research Safety Science Seminal Stains System TP53 gene Targeted Research Techniques Technology Testing Time Tissues Toxicology Whole Organism Work base body system chemokine complex biological systems consumer product cost cytokine cytotoxicity design drug candidate genotoxicity improved in vitro Model in vivo interest medication safety miniaturize model development monolayer novel novel strategies phase 2 study response safety assessment safety study safety testing screening success three dimensional cell culture three-dimensional modeling tissue culture tool tool development virtual

项目摘要

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.

项目摘要在简单的2D培养系统中研究细胞具有许多优点，能够在短时间内筛选许多条件，有针对性地添加或删除基因、蛋白质或其他成分的研究，以及对特定途径的重点研究只代表少数人。然而，这种简单性也可能导致关键功能的丢失和整个生物体尤其是人类的整体关联性缺乏。为了努力在培养皿中的细胞和人类之间架起一座桥梁，模拟整个器官的功能，即所谓的器官型培养。这些模型为研究高度复杂的多细胞系统提供了机会它的反应更像真正的器官，而不是在简单的单层我们的研究将建立大鼠肝细胞三维生长模型，格式化并与高效、高内容的分析平台配对，关于DNA功能和细胞健康的信息。这类模型的价值在于对基础科学和更有针对性的研究工作，如人类安全性研究。评估化合物的安全性，如候选药物，工业化学品和消费品依赖于临床前测试模型来报告有用的人类安全的信息。基于细胞的模型能够做到这一点，当体外和体内系统缺乏与人类的足够相关性时，条件所提出的3D器官模型可以克服现有的限制，并且结果降低成本，同时提供更好的信息。结合数据丰富的分析能够快速有效地评估体外动物源性器官模型代表了一个改善安全测试和创建工具的机会，许多其他的研究项目都依赖于体外系统。