Metabolism in Action: Quantitative Fluxes in Mammals

作用中的新陈代谢：哺乳动物体内的量化通量 摘要 参与新陈代谢的分子连接是所有主要的 生化网络。然而，代谢性疾病仍处于流行水平，而其他 涉及异常新陈代谢的疾病，如癌症，继续有增无减。关键的一步 要解决这些主要的未得到满足的医疗需求，就是理解 代谢途径，以及饮食和疾病对代谢途径的调节。尽管最近重振旗鼓 对新陈代谢的兴趣，系统水平的方法测量完整的新陈代谢活动 哺乳动物仍处于婴儿期。在这里，我建议将同位素追踪、最先进的 代谢组学技术，以及揭示整体代谢活动的计算模型 身体水平。标记的营养素将被静脉注射到小鼠体内，组织样本，以及 液-质联用法定量检测代谢物。代谢途径 将在全身范围内确定与示踪剂数据一致的流量(流量) 代谢模型，它包含组织特定的代谢活动和交换 器官之间通过循环的代谢物。通量还将受到以下因素的限制 宏观测量，如食物和氧气摄取量以及二氧化碳和尿素排出量 速率，将我们的方法与经典的生理测量方法联系在一起。通过这些研究，我们 将从定量的角度重新审视哺乳动物新陈代谢的整体运作。 预期结果包括加强对来源和消费途径的了解 循环代谢物，发现连接不同器官的新代谢周期，以及 广泛适用于疾病模型探索的定量测量方法。应用程序 这些方法将揭示疾病特异性途径的失调。总体影响将是 更全面、更全面地了解新陈代谢，从而实现合理饮食 对多种疾病进行指导和治疗干预。

Metabolism in Action: Quantitative Fluxes in Mammals Abstract The molecular connections involved in metabolism are the best understood of any major biochemical network. Nevertheless, metabolic disease remains at epidemic levels, and other diseases involving aberrant metabolism, such as cancer, continue unabated. A key step towards addressing these major unmet medical needs is to understand the integrated activity of metabolic pathways, and their modulation by diet and disease. Despite the recent revitalized interest in metabolism, systems-level methods for measuring metabolic activity in intact mammals remain in their infancy.Here I propose to combine isotope tracing, state-of-the-art metabolomics technology, and computational modeling to reveal metabolic activity at the whole body level. Labeled nutrients will be infused intravenously into mice, tissues sampled, and metabolite labeling quantified by liquid chromatography-mass spectrometry. Metabolic pathway flows (fluxes) consistent with the tracer data will be identified within the context of whole body metabolic model, which encompasses tissue-specific metabolic activity and exchange of metabolites between organs via the circulation. The fluxes will also be constrained by macroscopic measurements like food and oxygen uptake and carbon dioxide and urea excretion rates, tying our approach to classical physiological measurements. Through these studies, we will revisit from a quantitative perspective the overall operation of mammalian metabolism. Anticipated outcomes include enhanced understanding of the sources and consumption routes of circulating metabolites, discovery of novel metabolic cycles connecting different organs, and quantitative measurement methods of broad utility for probing disease models. Application of these methods will reveal disease-specific pathway dysregulation. The overall impact will be a more holistic and comprehensive understanding of metabolism that enables rational dietary guidance and therapeutic intervention across a broad spectrum of diseases.