Development of a human hepatocyte predictive pharmacology and toxicology system.

描述(申请人提供)：迫切需要通过开发更有效地模拟人体体内环境的人体肝细胞(肝脏)体外培养系统来提高临床前药物疗效和毒性筛选和测试的准确性。HemoSher是一家生物技术研究公司，利用专利方法在体外恢复对人类原代细胞的活体反应。在第一阶段SBIR R43DK091104下，我们开发了一个预测性的大鼠原代肝细胞系统，该系统可以在更接近体内的水平上恢复形态、功能、运输、代谢以及对药物和生长因子的反应。开发大鼠系统的原则，转化为人类原代肝细胞，在人类体内实现的药物水平上恢复形态、功能、新陈代谢和药物反应。据我们所知，目前还没有商业上可用的系统可以在人体原代肝细胞体外达到这种水平的肝生物学和体内反应。第二阶段SBIR R44DK091104的目的是进一步开发和验证可预测的原代人类肝细胞系统，以便与我们的商业合作伙伴一起用于毒理学研究、安全性评估和药物发现。我们的目标将使用集成的实验、基因组和计算方法来实现这一点，筛选系统中的40多种化合物。

DESCRIPTION (provided by applicant): There is a critical need to improve the accuracy of preclinical drug efficacy and toxicity screening and testing through the development of human hepatocyte (liver) in vitro culture systems that more effectively mimic the human in vivo environment. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. Under Phase I SBIR R43DK091104, we developed a predictive rat primary hepatocyte system that restores morphology, function, transport, metabolism and respond to drugs and growth factors at nearer to in vivo levels. The principles to develop the rat system, translated to human primary hepatocytes, restoring morphology, function, metabolism and drug response at in vivo drug levels achieved in humans. To our knowledge, there are no commercially available systems that can achieve this level of hepatobiology and in vivo responsiveness in human primary hepatocytes ex vivo. The purpose of Phase II SBIR R44DK091104 is to further develop and validate a predictive primary human hepatocyte system for use in investigative toxicology, safety assessment and drug discovery with our commercial partners. Our Aims will achieve this using an integrated experimental, genomic and computational approach, screening more than 40 compounds in the system.