Multiplexed high-content assay for toxicity profiling using live iPSC-derived cardiomyocyte lines with lineage-specific barcoding

使用具有谱系特异性条形码的活 iPSC 衍生心肌细胞系进行多重高内涵分析，进行毒性分析

• 批准号: 9761607
• 负责人: Mary Ludlam
• 金额: $ 82.16万
• 依托单位: CAIRN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761607
• 关键词: Address; Biological Assay; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell Line; Cell Lineage; Cells; Cellular Assay; Cellular Structures; Chemicals; Classification; Contracts; Data; Development; Drug Modelings; Drug toxicity; Effectiveness; Europe; Evaluation; Foundations; Generations; Goals; Government Agencies; Health Benefit; Heart Atrium; Human; In Vitro; Industry Standard; Machine Learning; Medicine; Methods; Microscopy; Mitochondria; Nodal; Nuclear; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiological; Population Heterogeneity; Positioning Attribute; Public Health; Reagent; Reporter; Reporting; Research; Safety; Sarcomeres; Site; Small Business Innovation Research Grant; Specificity; Speed; Structure; Testing; Time; Toxic effect; Toxicity Tests; Toxicology; Training; Treatment-Related Cancer; Validation; Ventricular; Withdrawal; Work; base; cell immortalization; clinical candidate; clinical predictors; cost; cost effective; drug discovery; drug testing; environmental chemical; expression vector; genome editing; high throughput screening; immortalized cell; improved; induced pluripotent stem cell; innovation; innovative technologies; machine learning algorithm; model development; new technology; novel; novel strategies; phase I trial; pre-clinical; predictive modeling; predictive test; predictive tools; programs; response; safety assessment; screening; site-specific integration; success; therapeutic development; therapeutic evaluation; tool

Project Summary/Abstract Human induced pluripotent stem cells (hiPSCs) are poised to transform toxicological evaluation, however new approaches to enable their functional and structural profiling are needed to improve the utility of hiPSC -based models for predictive and mechanistic toxicology screening. This need is addressed by our project’s Specific Aims that encompass (1) development of a novel platform for generation of hiPSC-derived reporter cells; (2) generation of a panel of multicolor hiPSC-derived cardiomyocytes (hiPSC-CMs) with stable lineage specific fluorescent reporters; and (3) implementation and validation of a pilot machine learning-enabled predictive cardiotoxicity screen using these tools. The proposed tools are configured to be extensible to other toxicology- relevant pathways and phenotypes making it uniquely positioned to capitalize on the growing commercial need for high-throughput predictive toxicology assays. The project deliverables benefit public health by improving the ability to rapidly identify liabilities in specific cardiomyocyte lineage types, thus reducing the time and cost to pinpoint cardiotoxicity of pharmaceutical and environmental chemicals.

项目概要/摘要 人类诱导多能干细胞 (hiPSC) 有望改变毒理学评估，无论多么新 需要能够进行功能和结构分析的方法来提高基于 hiPSC 的实用性 用于预测和机械毒理学筛选的模型。我们的项目的具体要求解决了这一需求 目标包括 (1) 开发用于生成 hiPSC 衍生报告细胞的新平台； (2) 生成一组具有稳定谱系特异性的多色 hiPSC 衍生心肌细胞 (hiPSC-CM) 荧光记者； (3) 实施和验证基于机器学习的预测试验 使用这些工具进行心脏毒性筛查。所提议的工具被配置为可扩展到其他毒理学- 相关途径和表型使其具有独特的优势，可以利用不断增长的商业需求 用于高通量预测毒理学测定。该项目可交付成果通过改善 能够快速识别特定心肌细胞谱系类型中的负债，从而减少时间和成本 查明药物和环境化学品的心脏毒性。