Integrated Transporter Elucidation Center

项目摘要/摘要 考虑到它们的物理化学性质，药物和膳食补充剂通常需要主动转运 溶质载体(SLC)和三磷酸腺苷结合盒(ABC)转运体跨越滋养层屏障。这些是相同的 转运蛋白还参与向胎儿输送营养物质，以及药物的一个无意后果。 怀孕期间的治疗可能会扰乱这些共享系统。因此，理解这种相互作用 SLC和ABC转运蛋白在胎盘药物和营养物质分配中的作用是优化的关键一步 改善围产期保健的治疗干预。我们的研究团队支持这一进步 研究胎盘中SLC和ABC转运蛋白的新方法。为了扩大这些努力，我们创建了 集成传输器说明中心(INTEC)利用4个领域的翻译研究专业知识 学术机构。我们的中心假设是胎盘转运蛋白的新调节和功能 可以使用综合的实验、流行病学和建模方法来阐明。一起， 生成的数据和模型可以预测胎盘对治疗药物和营养素的处置以及它们的 对胎儿发育的后续影响。为了实现这一目标，我们将1)确定规范 利用最先进的定量靶向绝对蛋白质组学和遗传学研究美国的胎盘转运蛋白 出生队列；2)开发一种新的预测母婴化学倾向的计算模型框架 根据胎盘转运蛋白的功能和调节；3)评价小说中SLC和ABC的转运蛋白 芯片上胎盘微生理系统。我们将测试营养素、补充剂、药物和毒物 胎盘转运蛋白的底物和抑制剂。INTEC将实现胎盘转运体的快速加速 研究并建立转运蛋白生物学的最佳实践。资源和数据集将通过我们的 CIIPro WebPortal2017年创建。将为早期职业科学家提供独特的培训机会 (本科生、硕士/硕士/博士研究生和博士后)和临床医生(产科住院医生和 在药理学、计算生物学、公共卫生、母婴医学和 生物医学工程学。通过创新的研究和培训，INTEC将在 在胎盘运输领域，确保训练有素的劳动力，以改善孕产妇和围产期健康。

PROJECT SUMMARY/ABSTRACT Given their physiochemical properties, medications and dietary supplements often require active transport using solute carriers (SLC) and ATP-binding cassette (ABC) transporters to cross trophoblast barriers. These same transporters are also involved in the delivery of nutrients to the fetus and one unintentional consequence of drug therapy during pregnancy can be disruption of these shared systems. Therefore, understanding the interplay between SLC and ABC transporters in the placental disposition of drugs and nutrients is one key step to optimizing therapeutic interventions that improve perinatal healthcare. Our research team has championed the advancement of novel approaches to study SLC and ABC transporters in the placenta. To expand these efforts, we have created the Integrated Transporter Elucidation Center (InTEC) which leverages translational research expertise across 4 academic institutions. Our central hypothesis is that novel regulation and functions of placental transporters can be elucidated using integrated experimental, epidemiological, and modeling approaches. Together, data and models generated can predict the placental disposition of therapeutics and nutrients and their subsequent effects on fetal development. To accomplish this goal, we will 1) identify critical factors that regulate placental transporters using state-of-the-art quantitative targeted absolute proteomics and genetics in a US-based birth cohort; 2) develop a novel computational modeling framework that predicts maternal-fetal chemical disposition according to placental transporter functions and regulation; and 3) evaluate SLC and ABC transport in novel placenta-on-a-chip microphysiological systems. We will test nutrients, supplements, drugs, and toxicants as substrates and inhibitors of placental transporters. InTEC will enable rapid acceleration of placenta transporter research and establish best practices for transporter biology. Resources and datasets will be disseminated via our CIIPro webportal created in 2017. Unique training opportunities will be provided to early career scientists (undergraduate students, MS/MPH/PhD students, and postdoc fellows) and clinicians (obstetrics residents and fellows) at the intersections of pharmacology, computational biology, public health, maternal-fetal medicine, and biomedical engineering. Through innovative research and training, InTEC will lead to novel breakthroughs in the field of placental transport and ensure a well-trained workforce to improve maternal and perinatal health.