Metabolism in Action: Quantitative Fluxes in Mammals

新陈代谢在行动：哺乳动物的数量通量

• 批准号: 9535989
• 负责人: JOSHUA D RABINOWITZ
• 金额: $ 113.4万
• 依托单位: PRINCETON UNIVERSITY
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535989
• 关键词: Address; Biochemical; Blood Circulation; Carbon Dioxide; Cardiovascular Diseases; Computer Simulation; Consumption; Data; Diabetes Mellitus; Diet; Disease; Disease model; Epidemic; Excretory function; Food; Intervention; Intravenous; Isotopes; Knowledge; Label; Malignant Neoplasms; Mammals; Measurement; Measures; Medical; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Modeling; Modernization; Molecular; Mus; Nerve Degeneration; Nutrient; Obesity; Organ; Outcome; Oxygen; Pathway interactions; Physiological; Route; Source; System; Technology; Therapeutic Intervention; Tissue Sample; Tissues; Tracer; Urea; infancy; interest; liquid chromatography mass spectrometry; metabolomics; novel; operation; uptake

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.

代谢的作用：哺乳动物的定量通量 摘要 新陈代谢中涉及的分子联系是任何主要的 生化网络尽管如此，代谢性疾病仍处于流行水平， 涉及异常代谢的疾病，如癌症，继续有增无减。一个关键步骤 解决这些主要的未满足的医疗需求的方法是了解 代谢途径，以及饮食和疾病对它们的调节。尽管最近振兴了 感兴趣的代谢，系统水平的方法来测量代谢活动的完整 哺乳动物仍然处于婴儿期。在这里，我建议结合联合收割机同位素示踪， 代谢组学技术和计算建模，以揭示代谢活动的整体 身体水平。标记的营养素将静脉输注到小鼠体内，组织取样， 通过液相色谱-质谱法定量代谢物标记。代谢途径 将在整个物体的范围内确定与示踪剂数据一致的流动（通量） 代谢模型，包括组织特异性代谢活性和 通过循环在器官之间代谢。通量也将受到 宏观测量，如食物和氧气的吸收以及二氧化碳和尿素的排泄 率，将我们的方法与经典的生理测量联系起来。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。 预期成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循环， 用于探测疾病模型的广泛实用的定量测量方法。的应用 这些方法将揭示疾病特异性途径失调。总体影响将是 更全面和全面地了解新陈代谢，使合理的饮食 指导和治疗干预广泛的疾病。