SBIR Phase I: Optimization of a Microscale Human Liver Tissue for Evaluating Chronic Drug Toxicity

SBIR 第一阶段：优化微型人体肝脏组织以评估慢性药物毒性

• 批准号: 0810551
• 负责人: Salman Khetani
• 金额: --
• 依托单位: HEPREGEN
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0810551&HistoricalAwards=false
• 关键词: SBIR; Phase; Optimization; Microscale; Human

This Small Business Technology Transfer Phase I project optimizes an in vitro model of human liver tissue and assess its utility for evaluating liver toxicity following chronic drug exposure. While primary human hepatocytes isolated from the liver are utilized by pharmaceutical and biotech industries to evaluate drug metabolism and toxicity, these cells under conventional culture rapidly lose liver-specific functions, which does not allow for chronic effects of drugs to be tested earlier in drug development. Recently, a miniaturized, multiwell human liver tissue model with defined microscale architecture has been developed that maintains phenotypic functions for several weeks. This project will utilize microtechnology tools to functionally optimize the microscale liver tissue for enhanced longevity (months), and assess utility of the system for evaluating clinically-relevant chronic (weeks) drug toxicity using high content imaging readouts and gene expression signatures.The broader impacts of this research are to provide an improved understanding of protein/gene expression changes in primary human hepatocytes following chronic drug exposure, and development of a novel chronic toxicity assay for use in industry. In the future, chronic toxicity screening with microscale liver tissues may be used to eliminate toxic compounds much earlier in the drug development pipeline towards reducing the $1 billion per drug development costs, increasing likelihood of clinical success, and limiting human exposure to unsafe drugs. More broadly, microscale human liver tissues may enable the investigation of mechanisms of toxicant action, allow identification of new biomarkers, and enable studies to assess the risk associated with exposure to mixtures of drugs.

这个小企业技术转移第一阶段项目优化了人类肝脏组织的体外模型，并评估了它在评估慢性药物暴露后肝脏毒性方面的效用。虽然从肝脏中分离的原代人肝细胞被制药和生物技术行业用于评估药物代谢和毒性，但这些细胞在常规培养下会迅速失去肝脏特异性功能，这使得药物的慢性效应无法在药物开发的早期进行测试。最近，一种小型化的、多孔的人肝组织模型已经被开发出来，该模型具有明确的微尺度结构，可以维持数周的表型功能。该项目将利用微技术工具对微尺度肝组织进行功能优化，以延长寿命（月），并利用高含量成像读数和基因表达特征评估该系统在评估临床相关慢性（周）药物毒性方面的效用。这项研究更广泛的影响是提供了对慢性药物暴露后原代人肝细胞中蛋白质/基因表达变化的更好理解，并开发了一种用于工业的新型慢性毒性测定方法。在未来，微尺度肝组织的慢性毒性筛选可能用于在药物开发管道中更早地消除有毒化合物，以减少每个药物开发成本10亿美元，增加临床成功的可能性，并限制人类接触不安全药物。更广泛地说，微型人体肝脏组织可能使毒性作用机制的研究成为可能，允许鉴定新的生物标志物，并使研究能够评估与暴露于药物混合物相关的风险。