Elucidating the mechanism behind oscillation between glycolysis and gluconeogenesis

阐明糖酵解和糖异生之间振荡背后的机制

• 批准号: 10436979
• 负责人: Junyoung O. Park
• 金额: $ 37.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436979
• 关键词: Adopted; Biomass; Biotechnology; Carbon; Carbon Dioxide; Control Groups; Diabetes Mellitus; Disease; Economics; Engineering; Enzymes; Gluconeogenesis; Glucose; Glycolysis; Glycolysis Pathway; Goals; Human; Isotopes; Kinetics; Malignant Neoplasms; Mammalian Cell; Maps; Mathematics; Measures; Medicine; Metabolic Control; Metabolic Pathway; Metabolism; Microbe; Mind; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Property; Regulation; Research; Research Personnel; System; Techniques; Technology; Thermodynamics; Tracer; blood glucose regulation; experimental group; innovation; knowledge of results; liquid chromatography mass spectrometry; mathematical model; metabolic engineering; microbial; new technology; novel; oxidation; programs; therapeutic development

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.

项目概要 帕克实验室的总体研究目标是获得系统级的理解 新陈代谢（包括其调节）并合理设计哺乳动物和微生物 我们是一支思想开放、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 经济和环境效益；并阐明热力学和动力学模式 哺乳动物糖异生的代谢控制是我们未来五年的目标之一。 开发关键技术以数学方式重建人类中心碳代谢 直到最近，代谢的表征仍然依赖于热力学和动力学术语。 主要是对照和对照之间的相对代谢物和酶水平的比较 我们将不仅仅测量“水平”，还会量化比率和 能量，直接代表新陈代谢的作用，但难以测量 因为它们是实质性的但却是无形的。为此，我们将采用最先进的液体。 色谱-质谱分析、数学建模和新型同位素示踪剂 我们的目标是在细胞代谢中应用最多的热力学和动力学信息。 这些技术研究了两个中心代谢途径：糖酵解和 这两种途径在很大程度上共享共同的酶组，但前者。 将葡萄糖转化为细胞能量和生物质前体，而后者则转化为非 这些功能相反的代谢途径支持碳水化合物底物转化为葡萄糖。 人类的全身葡萄糖稳态，以及微生物中的各种生物产品的合成 该项目将绘制具有不同氧化程度的各种碳底物的动力学图。 和哺乳动物细胞中两条途径的热力学瓶颈并阐明 实现它们之间无缝过渡和协调的监管机制。 这些通路的失调与 II 型糖尿病和癌症有关，我们认为 该研究计划将带来有效的代谢控制和工程策略 治疗疾病中碳代谢缺陷成功完成的结果。 拟议的研究将有助于推进糖尿病和糖尿病的治疗发展 癌症。