外排转运蛋白是原核和真核细胞的基本组成部分,在维持细胞稳态中起着至关重要的作用,代表了单细胞和群体水平之间的关键桥梁。从生物医学的角度来看,它们在耐药性(尤其是多重耐药性,MDR)在一系列跨越细菌和人类癌细胞的系统中。通常,这些细胞中存在多种外排转运蛋白,和外排转运蛋白运输一系列底物(转运蛋白之间的底物部分重叠)。此外,在抗药性的背景下,转运蛋白的水平可能由于额外或细胞内因素(前馈调节)或由于药物本身(反馈调节)而升高。因此,确实需要对一组运输者的集体功能及其对一种或多种药物的反应进行透明的系统级理解。我们为此开发了一个系统框架,并检查了运输机组的功能,它们与一种或多种药物的相互作用及其调节(前馈和反馈)。利用计算和分析工作,我们从药物和转运蛋白的多重性之间的相互作用中获得了一套转运蛋白的系统级功能的透明见解,不同的药物-转运蛋白相互作用参数,隔离、反馈和前馈调节。这些见解透明地源于对多种转运蛋白的最基本考虑,在自然生物学中具有广泛的相关性。生物医学工程和合成生物学。洞察力,创新,整合:创新:创建一个结构化的系统框架,用于评估多种转运蛋白对药物外排和耐药性的影响。系统分析使我们能够评估多种转运蛋白对一种/多种药物的影响,并解剖相关的抗性机制。整合可以阐明关键的因果关系,并对运输者的集体功能及其对阻力的影响进行透明的系统级理解,揭示关键潜在因素的相互作用。系统层面的见解包括作为一个组的一部分的转运蛋白的本质上不同的行为;流入的非直觉效应;前馈和药物诱导机制对转运蛋白水平升高的影响。相关性:系统对外排的理解,它们在MDR中的作用,提供用于设计治疗的框架/平台,和合成生物学设计。
Efflux transporters are a fundamental component of both prokaryotic and eukaryotic cells, play a crucial role in maintaining cellular homeostasis, and represent a key bridge between single cell and population levels. From a biomedical perspective, they play a crucial role in drug resistance (and especially multi-drug resistance, MDR) in a range of systems spanning bacteria and human cancer cells. Typically, multiple
efflux transporters are present in these cells, and the
efflux transporters transport a range of substrates (with partially overlapping substrates between transporters). Furthermore, in the context of drug resistance, the levels of transporters may be elevated either due to extra or intracellular factors (feedforward regulation) or due to the drug itself (feedback regulation). As a consequence, there is a real need for a transparent systems-level understanding of the collective functioning of a set of transporters and their response to one or more drugs. We develop a systems framework for this purpose and examine the functioning of sets of transporters, their interplay with one or more drugs and their regulation (both feedforward and feedback). Using computational and analytical work, we obtain transparent insights into the systems level functioning of a set of transporters arising from the interplay between the multiplicity of drugs and transporters, different drug-transporter interaction parameters, sequestration and feedback and feedforward regulation. These insights transparently arising from the most basic consideration of a multiplicity of transporters have broad relevance in natural biology, biomedical engineering and synthetic biology. Insight, Innovation, Integration: Innovation: creating a structured systems framework for evaluating the impact of multiple transporters on drug
efflux and drug resistance. Systematic analysis allows us to evaluate the effect of multiple transporters on one/more drugs, and dissect associated resistance mechanisms. Integration allows for elucidation of key cause-and-effect relationships and a transparent systems-level understanding of the collective functioning of transporters and their impact on resistance, revealing the interplay of key underlying factors. Systems-level insights include the essentially different behaviour of transporters as part of a group; unintuitive effects of influx; effects of elevated transporter-levels by feedforward and drug-induced mechanisms. Relevance: a systems understanding of
efflux, their role in MDR, providing a framework/platform for use in designing treatment, and in synthetic biology design.