Linking metabolic activity with drug sensitivity using metabolic influence networks

项目摘要 细胞代谢对药物敏感性的影响已经在广泛的生物体和 单元类型。然而，新陈代谢如何影响不同类别药物的活性尚未得到证实。 系统地探索。由于两者的影响，将新陈代谢和药物敏感性联系起来一直是一个挑战 新陈代谢对众多细胞过程的影响，以及药物反应的复杂性。为了解决这个问题，一个 尖端实验和计算系统的结合-生物学工具将被应用于解剖 细胞新陈代谢影响药物活性的机制。我实验室的总体目标是 开发系统生物学算法来重建代谢调节，并将其用于药物发现。这里 我们建议开发一种新的方法，将新陈代谢与各种细胞过程联系起来，称为新陈代谢 影响网络‘。我们将用它来预测细胞新陈代谢活动对抑制多种药物的影响 细胞过程。这一框架将应用于大肠杆菌、酵母和人类细胞系，使我们能够揭示 将新陈代谢与针对细胞过程的药物的效力联系起来的保守原则，如 复制、转录或信号传递。这一方法将通过改变细胞代谢来进行实验测试 营养筛选、酶抑制剂和药物组合的状态和药物敏感性。我们的系统 这种方法将使我们能够量化细胞代谢对药物作用的无数影响，包括摄取， 附带的相互作用和外流。最终，这个研究项目可以通过以下方式帮助精准医学的努力 基于细胞代谢活动和体内代谢环境的匹配治疗。

Project Summary The impact of cellular metabolism on drug susceptibility has been observed in a wide range of organisms and cell types. However, how metabolism influences the activity of diverse classes of drugs has not been systematically explored. Linking metabolism and drug sensitivity has been a challenge due to both the impact of metabolism on numerous cellular processes, and the complexity of drug response. To address this, a combination of cutting-edge experimental and computational systems-biology tools will be applied to dissect the mechanisms by which cellular metabolism impacts the activity of drugs. The overall goal of my lab is to develop systems biology algorithms to reconstruct metabolic regulation and harness it for drug discovery. Here we propose to develop a new approach to link metabolism with various cellular process, called the ‘metabolic influence network’. We will use it to predict the impact of metabolic activity of a cell on drugs that inhibit diverse cellular processes. This framework will be applied to E. coli, yeast and human cell lines, allowing us to uncover conserved principles linking metabolism with potency of drugs that target cellular processes such as replication, transcription or signaling. This approach will be tested experimentally by altering cellular metabolic state and drug sensitivity with nutrient screens, enzyme inhibitors and drug combinations. Our systems approach will allow us to quantify the myriad effects of cell metabolism on drug action, including uptake, collateral interactions, and efflux. Ultimately, this research program can help precision medicine efforts by matching therapy based on cellular metabolic activity and the in vivo metabolic environment.