Real Time Elucidation of Drug-Drug Interactions via Dual Reporter Cell Technology and Microfabricated Arrays

随着越来越多的美国人为了自己的健康服用一种以上的药物， 由于药物与药物的相互作用，不良事件的风险增加。新工具有 在药物代谢过程开始时理解生物学所必需的，即， 转录调控。因为多个酶可能作用于给定药物，且多个 转录因子可以激活一种酶，问题就变得相当复杂。此外, 重现人类生理学的新的体外组织工程模型需要 获得药物在体内反应的准确近似值。我们建议扩展到 以肝微生理体外模型芯片阵列为研究对象的高通量 酶的转录活性，并将其应用于药物-药物相互作用(DDIS)的研究。我们的 组织工程构建将同时使用原代人类细胞和诱导的多能干细胞 细胞(IPSC)-衍生细胞。该项目将由不同的研究小组进行。私人投资促进局 有很强的协作成就记录。马丁·雅穆什博士(MGH)将 监督芯片上肝脏的组织工程和药物相互作用研究。穆罕默德博士 麻省理工学院生物微机械资源中心主任托纳将领导微加工小组 重点研究了微细加工阵列的发展。IPSC来源的细胞将来自 来自约翰·霍普金斯大学的尹勇章博士。

With the number of Americans who take more than one drug for their well-being increasing, there is an increasing risk of adverse events due to drug-drug interactions. New tools are necessary to understand biology at the initiation of the drug metabolic process, i.e., transcriptional regulation. Since multiple enzymes may act on a given drug, and multiple transcription factors may activate an enzyme, the problem becomes quite complex. In addition, new in vitro tissue engineered models that recapitulate the human physiology are required to get an accurate approximation for the in vivo response of drugs. We propose to extend out microphysiological in vitro liver model to a liver-on-a-chip array to study in high-throughput the transcriptional activity of enzymes and apply it to the study of drug-drug interactions (DDIs). Our tissue engineered construct will use both primary human cells and induced pluripotent stem cells (iPSC)-derived cells. This project will be carried out by distinct research groups. The PIs have a very strong collaborative record of accomplishment. Dr. Martin Yarmush (MGH) will oversee tissue engineering of the liver-on-a-chip and the drug interaction studies. Dr. Mehmet Toner, Director of the BioMEMs Resource Center at MGH, will lead the microfabrication group focusing on the development of microfabricated array. The iPSC-derived cells will be sourced from Dr. Yoon Y Jang at Johns Hopkins University.