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

通过双报告细胞技术和微加工阵列实时阐明药物间相互作用

基本信息

批准号：
9767130
负责人：
Mehmet Toner
金额：
$ 45.08万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767130
关键词：
Activation Analysis Address Affect American Assessment tool Biology CAR receptor Cell Culture Techniques Cells Clinic Clinical Trials Coculture Techniques Communities Complex Data Data Set Development Dimensions Drug Exposure Drug Interactions Environment Enzymes Event Exposure to Fluorescence Focus Groups Future Genetic Transcription Goals Hepatocyte Human In Vitro Inflammation Inflammatory Injury Kupffer Cells Lead Lentivirus Infections Lentivirus Vector Libraries Liver Metabolism Microfabrication Modeling Molecular Pathogenesis Patient Representative Patients Personal Satisfaction Pharmaceutical Preparations Phase Physiological Physiology Play Public Health Reporter Reporting Research Resources Response Elements Role Signal Transduction Source Stimulus Subfamily lentivirinae System Technology Testing Time Time Study Tissue Engineering Tissues Toxic effect Transcriptional Activation Transcriptional Regulation Translating Universities Work adverse event risk constitutive androstane receptor culture plates design design and construction drug discovery drug metabolism drug testing enzyme activity experimental study genetic regulatory protein high throughput analysis improved in vivo induced pluripotent stem cell intercellular communication particle patient safety pre-clinical pregnane X receptor prevent promoter response stem therapeutic development tool transcription factor

项目摘要

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.

随着为了健康而服用一种以上药物的美国人数量不断增加，由于药物间相互作用，发生不良事件的风险不断增加。新工具是有必要了解药物代谢过程开始时的生物学，即转录调控。由于多种酶可能作用于一种给定的药物，并且多种转录因子可能会激活酶，问题就变得相当复杂。此外，需要新的体外组织工程模型来概括人体生理学获得药物体内反应的准确近似值。我们建议延长微生理体外肝脏模型到肝脏芯片阵列，以高通量研究酶的转录活性并将其应用于药物相互作用（DDI）的研究。我们的组织工程构建体将使用原代人类细胞和诱导多能干细胞细胞 (iPSC) 衍生的细胞。该项目将由不同的研究小组进行。 PI 拥有非常出色的协作成就记录。马丁·亚穆什 (Martin Yamush) 博士 (MGH) 将监督芯片肝脏的组织工程和药物相互作用研究。穆罕默德博士 MGH BioMEMs 资源中心主任 Toner 将领导微加工小组重点发展微阵列阵列。 iPSC 衍生细胞的来源来自约翰·霍普金斯大学的 Yoon Y Jang 博士。