Experimental and Theoretical Characterization of Metabolic Coordination

代谢协调的实验和理论表征

• 批准号: 1058793
• 负责人: Terence Hwa
• 金额: $ 36万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1058793&HistoricalAwards=false
• 关键词: Experimental; Theoretical; Characterization; Metabolic; Coordination

In this project, the PI will use a combination of experimental and theoretical approaches to revisit one of the intensively studied systems in molecular biology-catabolic repression. This is a widespread phenomenon whereby microorganisms grown in "good" (i.e., fast-growing) carbon sources such as glucose inhibit the synthesis of proteins needed for the consumption of "poor" (slow-growing) carbons. Despite a tremendous amount of knowledge characterized for this phenomenon at the molecular level for the bacterium E. coli, the "big picture" is still missing: In particular, what is this regulatory system for and how does the cell sense the quality of a carbon source? Based on a number of striking preliminary findings, the PI hypothesizes a radically different picture for the physiological function of catabolite repression, with its predominant role in coordinating the metabolism of carbon with other nutrient sources (e.g., nitrogen and sulfur), rather than in controlling the hierarchy of carbon metabolism. The PI will establish the new picture by quantitatively characterizing the expression of enzymes involved in carbon and nitrogen metabolism for a series of key mutants, under a variety of carbon-limiting and nitrogen-limiting conditions, paying special attention to changes in growth rates in the different growth conditions. The results will be analyzed by a phenomenological theory of exponential growth developed recently by the PI's lab. This research program will establish a new phenomenological approach to studying gene regulation and metabolism, an approach that involves very few parameters and is hence predictive. The simplicity of the approach will allow students with traditional biology training to grab the essence of quantitative physical reasoning, and allow students with physics training to learn a biological system in the context of physiology. The results of this research will exert a strong, transformative impact on the subject of metabolic regulation and more broadly on the field of quantitative biology. Due to the historical role catabolite repression played in the development of molecular biology, major revision in the understanding of this classic subject will also be noted broadly in other parts of the biology community. They will lend weight to the use of quantitative phenomenological approaches, which are very effective in elucidating complex physical systems but have so far seen very limited use in the study of biomolecular systems. Research output will be integrated into the PI's annual course on "quantitative biology", and the summer workshops the PI organizes for introducing physical scientists to quantitative biology.This project is being supported jointly by the Physics of Living Systems Program in the Physics Division and by Biomolecular Dynamics, Structure and Function in MCB.

在这个项目中，首席研究员将结合实验和理论方法，重新审视分子生物学中深入研究的系统之一——分解代谢抑制。 这是一种普遍现象，在“好”（即快速生长）碳源（例如葡萄糖）中生长的微生物会抑制消耗“差”（生长缓慢）碳所需的蛋白质合成。尽管在大肠杆菌的分子水平上对这种现象有大量的了解，但仍然缺乏“全局”：特别是，这个调节系统的作用是什么以及细胞如何感知碳源的质量？基于许多惊人的初步发现，PI对分解代谢物抑制的生理功能提出了截然不同的假设，其主要作用是协调碳与其他营养源（例如氮和硫）的代谢，而不是控制碳代谢的层次。 PI将通过定量表征一系列关键突变体在各种限碳和限氮条件下参与碳和氮代谢的酶的表达来建立新的图景，特别关注不同生长条件下生长速率的变化。 结果将通过 PI 实验室最近开发的指​​数增长现象学理论进行分析。 该研究计划将建立一种新的现象学方法来研究基因调控和代谢，这种方法涉及的参数很少，因此具有预测性。该方法的简单性将使接受过传统生物学训练的学生能够抓住定量物理推理的本质，并允许接受过物理训练的学生在生理学背景下学习生物系统。这项研究的结果将对代谢调节学科乃至更广泛的定量生物学领域产生强大的变革性影响。 由于分解代谢物抑制在分子生物学发展中发挥的历史作用，对这一经典主题的理解的重大修改也将在生物学界的其他部分引起广泛关注。它们将重视定量现象学方法的使用，这种方法在阐明复杂的物理系统方面非常有效，但迄今为止在生物分子系统的研究中的用途非常有限。研究成果将纳入 PI 的“定量生物学”年度课程，以及 PI 组织的夏季研讨会，向物理科学家介绍定量生物学。该项目得到了物理部门生命系统物理学项目和 MCB 生物分子动力学、结构和功能部门的共同支持。