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

• 批准号: 9356507
• 负责人: Mehmet Toner
• 金额: $ 45.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356507
• 关键词: Activation Analysis; Address; Adverse event; 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; Pharmaceutical Preparations; Phase; Physiological; Physiology; Play; Public Health; Reporter; Reporting; Research; Resources; Response Elements; Risk; 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; 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

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.

随着越来越多的美国人为了健康而服用一种以上的药物， 由于药物-药物相互作用，不良事件的风险增加。新工具 在药物代谢过程开始时了解生物学是必要的，即， 转录调控由于多种酶可作用于给定的药物，并且多种酶可作用于给定的药物。 转录因子可能激活酶，问题变得相当复杂。此外，本发明还提供了一种方法， 需要新的体外组织工程模型来概括人类生理学， 得到药物在体内反应的精确近似值。我们建议扩大 微生理学体外肝脏模型到肝芯片阵列，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 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。法律与正义党 有很强的合作成就记录Martin Yarmush博士（MGH）将 监督肝脏芯片的组织工程和药物相互作用研究。穆罕默德医生 MGH BioMEMs资源中心主任Toner将领导微加工组 专注于微加工阵列的开发。iPSC衍生的细胞将来源于 来自约翰霍普金斯大学的Yoon Y Jang博士。