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.

作用中的代谢：哺乳动物的定量通量 抽象的 代谢所涉及的分子连接是任何主要的理解 生化网络。然而，代谢疾病仍然处于流行水平，其他 涉及异常代谢（例如癌症）的疾病继续没有减弱。关键步骤 解决这些主要未满足的医疗需求是了解 代谢途径及其对饮食和疾病的调节。尽管最近振兴了 对代谢，系统级方法的兴趣，用于测量完整的代谢活性 哺乳动物仍处于婴儿期。我建议将同位素追踪结合起来 代谢组学技术和计算建模，以揭示整体代谢活动 身体水平。标记的营养素将静脉注入小鼠，采样组织，然后 由液相色谱 - 质谱法量化的代谢产物标记。代谢途径 与示踪剂数据一致的流（通量）将在整个身体的背景下识别 代谢模型，该模型包括组织特异性的代谢活性和交换 器官之间的代谢物通过循环。通量也将受到限制 宏观测量，例如食物和氧气吸收以及二氧化碳和尿素排泄物 费率，将我们的经典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代谢的整体运作。 预期的结果包括对来源和消费路线的增强理解 循环代谢产物，发现连接不同器官的新代谢周期的发现， 用于探测疾病模型的广泛实用性的定量测量方法。应用 这些方法将揭示特异性途径失调。总体影响将是 对新陈代谢的更全面和全面的理解，使饮食能够理性 各种疾病的指导和治疗干预。