Elucidating the mechanism behind oscillation between glycolysis and gluconeogenesis

项目摘要 帕克实验室的首要研究目标是获得系统级的理解， 代谢（包括其调节）和合理工程哺乳动物和微生物 生物技术和医学的新陈代谢。我们是一个开放的团队， 研究人员采用核心分析技术，不断创新（并采用）新的 技术，以解决与各种疾病和生物体相关的挑战性问题。 我们目前的研究是双重的：微生物转化二氧化碳为增值产品 的热力学和动力学模式， 在哺乳动物生殖过程中的代谢控制。我们未来五年的目标之一是 开发关键技术，以数学方式重建人类中心碳代谢， 热力学和动力学术语。直到最近，代谢的表征一直依赖于 主要是比较对照组和对照组之间的相对代谢物和酶水平， 实验组。我们将超越仅仅衡量“水平”，量化比率， 能量，这是直接代表新陈代谢的行动，但难以衡量 因为它们是实质性的，但又是无形的。为此，我们将采用最先进的液体 色谱-质谱法，数学建模，和新的同位素示踪剂，可以 产生细胞代谢中最多的热力学和动力学信息。我们的目标是应用 这些技术研究两个中心的代谢途径：糖酵解和 异源发生这两种途径在很大程度上共享一个共同的酶集，但前者 将葡萄糖转化为细胞能量和生物质前体，而后者将非 碳水化合物底物转化为葡萄糖。这些功能相反的代谢途径支持 人体和微生物中的全身葡萄糖稳态， 广泛的碳基质，具有不同的氧化程度。该项目将绘制动力学 和热力学瓶颈的两个途径在哺乳动物细胞和阐明 监管机制，使它们之间的无缝过渡和协调。作为 这些通路的失调与II型糖尿病和癌症有关，我们设想， 这项研究计划将导致有效的代谢控制和工程策略， 治疗疾病中有缺陷的碳代谢。成功地完成了 拟议的研究将有助于推进糖尿病的治疗发展， 癌

Project Summary The overarching research goal of the Park lab is to gain systems-level understanding of metabolism (including its regulation) and rationally engineer mammalian and microbial metabolism for biotechnology and medicine. We are a team of open-minded and hardworking researchers who employ core analytical techniques and ceaselessly innovate (and adopt) new technologies to solve challenging problems associated with various diseases and organisms. Our current research is twofold: microbial conversion of carbon dioxide into value-add products for economic and environmental benefits; and elucidation of thermodynamic and kinetic mode of metabolic control in mammalian gluconeogenesis. One of our goals over the next five years is to develop key technologies to mathematically reconstruct human central carbon metabolism in thermodynamic and kinetic terms. Until recently, characterization of metabolism has relied mainly on comparison of relative metabolite and enzyme levels between control and experimental groups. We will go beyond measuring just the “levels” and quantify rates and energies, which are direct representation of metabolism in action yet difficult to measure because they are substantive yet intangible. To this end, we will employ state-of-the-art liquid chromatography-mass spectrometry, mathematical modeling, and novel isotope tracers that can yield the most thermodynamic and kinetic information in cellular metabolism. We aim to apply these techniques to investigating the two central metabolic pathways: glycolysis and gluconeogenesis. The two pathways largely share a common enzyme set, yet the former converts glucose into cellular energy and biomass precursors while the latter converts non- carbohydrate substrates into glucose. These functionally opposite metabolic pathways support systemic glucose homeostasis in humans and, in microbes, various bioproduct synthesis from a wide range of carbon substrates with varying degrees of oxidation. This project will map kinetic and thermodynamic bottlenecks of the two pathways in mammalian cells and elucidate regulatory mechanisms that enable seamless transitions and coordination between them. As dysregulation of these pathways are implicated in type II diabetes and cancer, we envision that this research program will lead to effective metabolic control and engineering strategies to remedy defective carbon metabolism in diseases. The upshot of successfully completing the proposed research will contribute to advancing therapeutic development for diabetes and cancer.