Elucidating the mechanism behind oscillation between glycolysis and gluconeogenesis

项目摘要 PARK实验室的主要研究目标是获得系统级的了解 代谢(包括其调节)和合理设计哺乳动物和微生物 生物技术和医学的新陈代谢。我们是一支思想开放、工作勤奋的团队 采用核心分析技术并不断创新(和采用)新技术的研究人员 解决与各种疾病和生物体相关的挑战性问题的技术。 我们目前的研究有两个方面：微生物将二氧化碳转化为增值产品 为经济和环境效益；并阐明了热力学和动力学模式 哺乳动物糖异生中的代谢控制。我们未来五年的目标之一是 开发以数学方式重建人体中心碳代谢的关键技术 热力学和动力学术语。直到最近，对新陈代谢的描述还依赖于 主要比较对照组和对照组的相关代谢物和酶水平 试验组。我们将超越只测量“水平”的范围，量化利率和 能量，它是新陈代谢的直接代表，但很难测量 因为它们是实体的，但又是无形的。为此，我们将使用最先进的液体 色质联用、数学建模和新型同位素示踪剂 提供细胞新陈代谢的最多热力学和动力学信息。我们的目标是申请 这些技术用于研究两种中枢代谢途径：糖酵解和 糖异生作用。这两条途径在很大程度上共享一个共同的酶组，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 在人类体内的系统性葡萄糖稳态，以及在微生物中，从一种不同的生物产物合成 种类繁多的碳基材料，氧化程度不一。该项目将绘制动态地图 并阐明了哺乳动物细胞中这两条途径的热力学瓶颈 能够实现无缝过渡和它们之间协调的监管机制。AS 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战略 治疗疾病中存在的碳代谢缺陷。成功完成的结果是 拟议的研究将有助于推进糖尿病的治疗开发和 癌症。

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.